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. 2015 Mar 17;5(1):223–243. doi: 10.3390/biom5010223

Transcriptional Regulation of Chemokine Expression in Ovarian Cancer

Bipradeb Singha 1, Himavanth R Gatla 1, Ivana Vancurova 1,*
Editor: Jürg Bähler1
PMCID: PMC4384120  PMID: 25790431

Abstract

The increased expression of pro-inflammatory and pro-angiogenic chemokines contributes to ovarian cancer progression through the induction of tumor cell proliferation, survival, angiogenesis, and metastasis. The substantial potential of these chemokines to facilitate the progression and metastasis of ovarian cancer underscores the need for their stringent transcriptional regulation. In this Review, we highlight the key mechanisms that regulate the transcription of pro-inflammatory chemokines in ovarian cancer cells, and that have important roles in controlling ovarian cancer progression. We further discuss the potential mechanisms underlying the increased chemokine expression in drug resistance, along with our perspective for future studies.

Keywords: chemokines, interleukin-8, NFκB, ovarian cancer, transcriptional regulation

1. Introduction

Chemokines are a family of cytokines that induce chemotaxis of target cells. Though they were originally discovered for their ability to induce leukocyte migration into the infected or injured sites, more recently, it became clear that they could also promote cancer progression [1,2,3,4,5,6,7,8,9]. In addition to inducing tumor cell proliferation, angiogenesis and metastasis, chemokines and their receptors regulate tumor cell differentiation and survival. Currently, the human chemokine network includes more than 45 known chemokines and 20 chemokine receptors. Based on the number and spacing of conserved N-terminal cysteine residues that form disulfide bonds, chemokines are divided into four groups: (X)C, CC, CXC, and CX3C [10,11,12].

Epithelial ovarian cancer (EOC) is among the leading causes of cancer death in women. Since most ovarian cancers relapse and become drug-resistant, the survival rates remain low. Progression of ovarian cancer (OC) has been associated with the increased expression and release of pro-inflammatory chemokines, which contribute to ovarian cancer development through their induction of tumor cell proliferation, survival, migration, and angiogenesis [13,14,15]. The chemokine expression by ovarian cancer cells is controlled at several levels that include transcriptional regulation, post-transcriptional regulation and regulation of mRNA stability, translation, and mechanisms regulating the cytokine intracellular storage, transport, and release. Table 1 summarizes chemokines produced by ovarian cancer cells. Several excellent reviews have addressed the physiological and cellular functions of these chemokines in ovarian cancer [9,16,17]. Thus, in this review, we focus instead on the main mechanisms that regulate transcription of these chemokines in ovarian cancer cells.

Table 1.

Chemokines released by ovarian cancer cells.

Systematic Name Alternate Human Names Tissue/Cells Reference
CCL2 Monocyte chemotactic protein 1 (MCP-1) Tumor biopsies, serum and ascites Negus et al., 1995 [18]
Milliken et al., 2002 [19]
CCL5 RANTES Tumor ascites, plasma and peritoneal fluid Milliken et al., 2002 [19]
Negus et al., 1997 [20]
CCL11 Eotaxin Primary ovarian cancer cells obtained from ascites Levina et al., 2009 [21]
Nolen et al., 2010 [22]
CCL25 Thymus expressed chemokine (TECK) Tumor tissue Singh et al., 2011 [23]
CCL28 Mucosae-associated epithelial chemokine (MEC) Tumor tissue Facciabene et al., 2011 [24]
CXCL1 Growth-regulated protein α (GRO-α) Plasma and tumor ascites Lee et al., 2006 [25]
Yang et al., 2006 [26]
CXCL2 Growth-regulated protein β (GRO-β) Ovarian cancer cell lines Son et al., 2007 [27]
Kavandi et al., 2012 [28]
CXCL8 Interleukin 8 (IL-8) Tumor tissue, ascites, serum and cyst fluid Lee et al., 1996 [29]
Xu et al., 1999 [30]
CXCL12 Stromal cell-derived factor (SDF-1) Tumor biopsies, tissues and ascites Zou et al., 2001 [31]
Scotton et al., 2002 [32]
CXCL16 Transmembrane chemokine CXCL16 Epithelial ovarian carcinoma tissue Guo et al., 2011 [33]
Gooden et al., 2014 [34]
CX3CL1 Fractalkine Epithelial ovarian carcinoma tissue Gaudin et al., 2011 [35]
XCL1/2 Lymphotactin Tumor ascites and ovarian cancer cell lines Kim et al., 2012 [36]
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2. Mechanisms Regulating Chemokine Transcription in Ovarian Cancer Cells

2.1. Chemokine Regulation by NFκB and Epigenetic Acetylation

Chemokines are regulated at the transcriptional level by binding of transcription factors and repressors to gene promoter and enhancer regions. The transcription factors that control the expression of most inflammatory chemokines include the nuclear factor-κB (NFκB), activator protein-1 (AP-1) and the signal transducers and activators of transcription (STAT) family. The NFκB activity is constitutively increased in aggressive ovarian cancers, and inhibition of NFκB signaling suppresses angiogenesis and tumorigenicity of ovarian cancer cells and increases their sensitivity to chemotherapy and apoptosis [37,38,39,40]. The underlying mechanisms likely involve the NFκB-regulated chemokine expression, since several studies have demonstrated that the expression of CCL2, CXCL1, CXCL2, and IL-8/CXCL8 is mediated by NFκB in ovarian cancer cells [28,29,30,41].

The increased activity of NFκB in ovarian cancer cells is mediated by enzymes of the IκB kinase (IKK) complex, which phosphorylate the NFκB inhibitory protein, IκBα, resulting in IκBα proteasomal degradation and nuclear translocation of NFκB subunits [42,43,44,45]. In addition to phosphorylating IκBα, IKKs can also phosphorylate the NFκB subunits, particularly p65 [46]. While the cytoplasmic degradation of IκBα, resulting in the nuclear translocation of NFκB subunits, represents a general step in NFκB activation, the specificity of NFκB-regulated responses is mediated by the subunit composition of NFκB complexes and their post-translational modifications [47,48].

In addition to transcription factor binding to promoter sequences, chemokine expression is regulated by epigenetic modifications that include histone modifications as well as post-translational modifications of transcription factors, particularly the p65 subunit of NFκB. It is believed that while histone acetylation and acetylation of transcription factors induced by histone acetyl transferases (HATs) generally promotes transcriptional activation, hypoacetylation induced by histone deacetylase (HDAC) activity is associated with transcriptional repression. Since hypoacetylation of tumor suppressor genes by HDACs has been linked to tumor development, HDACs inhibitors are now being evaluated for their therapeutic effects in cancer, including ovarian cancer [49,50,51]. Clinical studies using HDAC inhibitors in the treatment of ovarian cancer are summarized in the recent elegant review by Khabele [52]. Numerous studies have shown that HDACs regulate chemokine expression in different cell types [53,54,55,56,57,58]; however, their role in the regulation of chemokine expression in ovarian cancer has yet to be documented.

2.2. Chemokine Modulation by Hypoxia and Metabolism

Ovarian cancer tissues and ascites are characterized by decreased oxygen content, which stabilizes the α-subunit of the transcription factor hypoxia-inducible factor-1 (Hif-1) [59]. Hif-1 responds to hypoxia by increasing the transcription of genes that promote survival in low-oxygen conditions, thus promoting angiogenesis and oncogenesis. Indeed, the increased expression of Hif-1 has been detected in epithelial ovarian cancer, and correlates with poor prognosis [60,61,62]. Hypoxia induces IL-8 [30], CXCL12 [63], and CCL28 [24] expression in ovarian cancer cells. The seminal study by Xu et al. [30] demonstrated that hypoxic conditions increase the IL-8 expression in ovarian cancer cells by increasing NFκB and AP-1 binding to IL-8 promoter. The mechanisms of how hypoxia increases the NFκB-dependent IL-8 transcription involve activation of the transforming growth factor beta-activated kinase 1 (TAK1), resulting in increased IKK activation, and p65 NFκB recruitment to the IL-8 promoter [64,65]. In addition, hypoxia induces a direct binding of Hif-1α to the hypoxia-response element (HRE) located next to the NFκB binding site in human IL-8 promoter, resulting in the increased IL-8 expression [66].

One of the consequences of Hif-1 activation is the increased expression of glycolytic genes, resulting in increased aerobic glycolysis, glucose consumption, and lactic acid production (Warburg effect) [67,68,69]. The high rate of glucose consumption and lactic acid production contributes to the acidification of the tumor environment and cancer progression. Xu et al. showed that acidic pH increases the IL-8 transcription by enhancing the binding of AP-1 and NFκB to IL-8 promoter in ovarian cancer cells [70]. In addition, in endothelial cells, lactate was shown to activate the NFκB-dependent IL-8 transcription by inducing degradation of IκBα [71]. The role of lactate and other metabolites of the glycolytic pathway in the regulation of pro-angiogenic chemokine expression in ovarian cancer cells is yet to be investigated, especially since recent studies have indicated high levels of aerobic glycolysis and lactate production in ovarian tumors [72,73].

While hyperglycemia and obesity are thought to be contributing factors to cancer development and progression, caloric restriction has been associated with reduced cancer incidence [74,75,76,77]. During reduced calorie intake or exercise, the body switches to obtaining energy from fatty acid oxidation, which results in ketone bodies production. Intriguingly, the recent study by Shimazu et al. [78] has demonstrated that the ketone body β-hydroxybutyrate (βOHB) is an endogenous and specific inhibitor of HDACs, and that administration of exogenous βOHB increases histone acetylation, correlating with changes in transcription. Since HDACs regulate chemokine transcription by both deacetylating histones and p65 NFκB [53,54,55,56,57,58], it will be important to analyze whether βOHB and other HDAC inhibitors regulate chemokine expression in ovarian cancer cells, and whether this is modulated by the metabolic state.

2.3. Chemokine Modulation by Chemotherapeutic Interventions

There is growing evidence that the increased chemokine expression by tumor cells modulates not only cancer development but also cancer responsiveness and resistance to chemotherapy [79]. A major contributor to the acquired chemoresistance of ovarian cancer cells is the increased expression of NFκB-dependent chemokines that is induced by the platinum-based drugs carboplatin and cisplatin, and by the mitotic inhibitors docetaxel and paclitaxel [29,80,81,82,83]. The mechanisms responsible for the increased IL-8 expression induced by paclitaxel in ovarian cancer cells involve increased expression of toll-like receptors (TLRs) and increased p65 NFκB binding to IL-8 promoter [80,83].

Bortezomib (BZ) is the first FDA approved proteasome inhibitor, which has shown a limited effectiveness in ovarian cancer treatment as a single agent [84,85,86,87]. However, BZ has been considered in combination with cisplatin, since BZ prevents the cisplatin-induced degradation of cisplatin influx transporter, resulting in enhanced cisplatin uptake and tumor cell killing [88,89]. We have recently shown that BZ increases expression of IL-8 and CCL2 in ovarian cancer cells, while it does not affect expression of other NFκB-dependent genes. The responsible mechanisms involve a gene specific and IKKβ-dependent recruitment of S536 phosphorylated p65 NFκB to IL-8 and CCL2 promoters, suggesting that anti-inflammatory therapy targeting IKKβ might increase the BZ effectiveness in ovarian cancer treatment [41]. Since approximately 50% of women diagnosed with ovarian cancer die from chemoresistant metastatic disease, understanding the molecular mechanisms by which chemotherapeutic interventions increase the chemokine expression in ovarian cancer cells should lead to the development of more effective combination strategies.

3. Chemokine Transcriptional Regulation in Ovarian Cancer Cells

Chemokines listed in Table 1 have all been identified in ovarian cancer cells and tissues. Various online databases can be used to assess putative transcription factor binding sites. For this review, we have obtained chemokine promoter sequences from the NCBI database and used the Alggen promoter-mapping program to search for the transcription factor binding sites [90,91]. All found putative binding sites are listed in Table 2, Table 3, Table 4 and Table 5; the binding sites that have been experimentally confirmed are highlighted in bold and labeled with an asterisk. Below, we limit discussion of the transcriptional mechanisms only to the chemokines that have been experimentally confirmed in ovarian cancer cells. While the first insights into the chemokine transcriptional regulation were obtained by using in vitro electrophoretic mobility shift assays (EMSA) or overexpression experiments, chromatin immunoprecipitations (ChIP) generally provides a more realistic picture about the transcription factor binding to endogenous promoter sequences in living cells.

Table 2.

List of putative transcription factor binding sites in human CCL2 promoter.

Factor Site Sequence Factor Site Sequence
SP-1 -54/-44 ACTCCGCCCT c-Fos -1465/-1457 CTGACTCC
Nkx-1 -65/-58 CCTCCTG p53 -1541/-1534 GGGCAGG
Elk-1 -76/-71 GGAAG HOX-11 -1571/-1564 CCTAACG
GATA -88/-82 CTTATC PEA3 -1644/-1636 AAACATCC
C/EBP -112/-106 TTGCTC GR -1790/-1782 TTGTTCTC
ELF -143/-130 CTACTTCCTGGAA AR -1789/-1781 TGTTCTCT
Hif-1 * -127/-122 CACAG FOXP3 -1959/-1950 AAACATTTT
AP-1 * -139/-131 TTCCTGGAA C/EBP -1980/-1973 TTGCACA
STAT1-3 * -139/-131 TTCCTGGAA Pbx-1 -2132/-2120 AGCATGACTGGA
C-Ets1 -140/-133 CTTCCTG FOXO-3 -2184/-2176 CTTATTTA
NF-AT -181/-172 GGAAAAAGT CUTL-1 -2309/-2303 ATTGGT
E47 -239/-232 GTCTGGG PR -2358/-2351 GAACACT
RP58 -256/-245 GTTCACATCTG Smad3 -2521/-2511 GAGGCAGACA
HNF-1 -654/-646 TAATATTT ERα -2570/-2562 CTGACCTC
TMF -708/-701 TATAACA c-Jun -2580/-2574 CATGGG
HNF-3 -742/-735 CTATTTA NFκB * -2600/-2591 GGAATTTCC
AP-2 -747/-741 GCAGGC ZDX/BCL6 -2632/-2621 GGGAACTTCC
c-Jun -942/-935 TGACTTA E47 -2678/-2671 ATCTGGA
HMG1 -1042/-1035 GGAAATT ETF -2717/-2708 CACAGCCCC
IRF-3 -1089/-1082 GCTTTCC GATA -2902/-2893 CTTTATCT
BTEB3 -1287/-1278 AGGAGGAGG PU-1 -3041/-3031 TTACTTCCTC
NF-Y -1315/-1307 ATTGGGCA YY1 -3264/-3257 AAAATGG
USF-2b -1447/-1439 GTCATTTG RAR -3429/-3421 ATCTCACC
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* Experimentally confirmed binding sites, Hif-1; Hypoxia inducible factor-1, AP-1; Activator protein-1, STAT1-3; Signal transducer and activator of transcription 1-3, NFκB; Nuclear factor kappa B.

Table 3.

List of putative transcription factor binding sites in human CXCL1 promoter.

Factor Site Sequence Factor Site Sequence
IRF-3 -50/-43 GCTTTCC Elk-1 -771/-766 GGAAG
HMG I -75/-68 AATTTCC FOXP3 -791/-782 CAACATTTT
MBP-1 -78/-68 GGGAATTTCC MZF-1 -810/-803 CAGGGGA
NFκB * -79/-68 CGGGAATTTCC TGIF -870/-862 TGACAACC
CDP * -97/-87 GGGATCGATC C/EBP -980/-974 TTGCAC
E47 -90/-83 ATCTGGA YY-1 -1061/-1054 TAAATGG
E2F-1 -126/-119 GGCGGGG c-Ets -1076/-1069 CAGGAAG
SP3 -128/-119 GGGGCGGGG AR -1394/-1386 TGTTCTCT
SP-1 * -130/-121 GGGGGCGGG c-Jun -1491/-1483 TGACTCAT
R2 -137/-131 TCCACC Pax -1909/-1902 CCTTGAC
LF-A1 -247/-240 TGGGGCA ERα -2057/-2050 TGGGTCAA
AP-2 * -279/-273 GCAGGC NF-Y -2060/-2052 ATTGGGTC
AREB6 -296/-288 CAGGTGGT LEF-1 -2807/-2799 CTTTGTTG
Smad3 -563/-553 TTCACAGACA HNF-1 -2966/-2958 TAATATTT
PR -602/-595 GAACATT RAR -3102/-3094 ATGCCTTAG
GR -605/-596 GCAGAACAT NHP-1 -3103/-3096 TGACCTT
TMF -739/-732 TGTTATA PEA3 -3110/-3102 GGATGTAT
GATA -767/-761 GATAAG ATF -3452/-3443 TGACGTAAA
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* Experimentally confirmed binding sites, CDP; CAATT displacement protein, SP-1; Specificity protein 1, AP-2; Activator protein 2.

Table 4.

List of putative transcription factor binding sites in human CXCL2 promoter.

Factor Site Sequence Factor Site Sequence
NFκB * -76/-67 GGGAATTTCC BTEB3 -862/-853 AAGCGGAGT
CREB -83/-74 CGGACGTCA NF-Y -970/-962 GAACCAAT
ATF-2 -83/-74 CGGACGTCA HMG I -999/-992 AATTTCC
HLF -104/-95 GTTACGCAA IRF -999/-992 AATTTCC
E2F-1 -111/-104 GGCGGGA NF-AT -1001/-992 AAAATTTCC
NF-1 -113/-108 TTGGC CUTL1 -1085/-1079 ATTGAT
LF-A1 -139/-132 CGGGGCA FOXP3 -1115/-1106 CTTAATTTT
GATA -192/-184 GGTTATCT PR A -1257/-1250 GAACACT
AP2α -198/-192 GCAGGC C/EBP -1367/-1360 TGAGCAA
STAT3 * -218/-210 TTGGGGAA MZF1 -1380/-1373 CAGGGGA
ERα -241/-233 CTGACCCA HNF-1 -1440/-1432 ATATTAAC
PEA3 -276/-268 GGATGTAG TMF -1880/-1873 TATAACA
Elk-1 -296/-292 GAAG E47 -1830/-1823 TTCTGGA
STAT3 * -318/-310 GGGATCGATC Nkx2 -1827/-1820 CTGGAGG
p53 -339/-332 CTTGCCC HNF -2153/-2146 TAAATGG
AhR -418/-410 GCGTGCGT YY1 -2153/-2146 TAAATGG
c-Jun * -437/-430 TGACACA HSF1 -2409/-2401 ATTCTAGG
c-Fos -451/-443 TGCGTCAT ETF -2505/-2496 GGGGCTGTC
c-Ets -473/-467 CAGGAAG AP3 -2636/-2629 GAGTTAG
USF-1 -508/-499 ACACGTGAT Smad3 -3112/-3102 CAGTCAGACA
AREB6 -574/-566 AACACCTG LEF-1 -3101/-3093 CAACAAAG
FOXJ2 -621/-611 AAAATAAACA TCF-1 -3102/-3093 ACAACAAAG
AR -673/-665 TGTTCCAA GR -3256/-3247 ACAGAACAT
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* Experimentally confirmed binding sites, c-Jun; Jun proto-oncogene.

Table 5.

List of putative transcription factor binding sites in human CXCL8 promoter.

Factor Site Sequence Factor Site Sequence
NFκB * -80/-70 GGAATTTCC E47 -859/-852 ATCTGGA
PU-1 -83/-73 GGAATTTCCTC PR -868/-861 ACTCTTC
NRF * -88/-77 ATTCCTCTGA HSF1 -867/868 CCTTGAAT
C/EBP * -94/-87 TTGCAAA IRF -973/-964 TTTCCATTA
MZF-1 -112/-105 GAGGGA RAR -1068/-1061 AGAGGTC
EBF -118/-107 TGCCCTGAGGG ERα -1067/-1060 GAGGTCA
C/EBP * -119/-112 TTGCACA p53 -1258/-1251 CTTGCCC
AP-1 * -129/-121 TGACTCAG FOXP3 -1304/-1295 AAAATGAAG
c-Ets -141/-132 TAGGAAGTC RelA -1367/-1357 GGCATTCCCC
Elk-1 -139/-134 GGAAG YY1 -1372/-1365 AAAATGG
LEF-1 -187/-179 GATCAAAG Smad3 -1403/-1393 GAAACAGACA
Hif-1 * -234/-229 GTGCG Nkx1 -1457/-1450 CCTCAAG
GRα -335/-327 TTGTTCTA AP2α -1473/-1467 CCAGGC
AREB6 -328/-320 AACACCTG TCF1 -1663/-1654 ACAACAAAG
AR -334/-326 TGTTCTAA NF-AT -1687/-1677 CTAATTTTCC
NF -424/-416 ATTGGCTC HMGI -1685/-1677 AATTTTCC
AP3 -535/-528 TAAATC HLF -1695/-1686 TTGTGTAAC
HNF-3 -606/-599 TAAATGT CUTL1 -1858/1852 TTGGT
FOXO3 -651/-641 CTTATCTA PEA3 -2174/-2166 GCACATCC
GATA -651/-644 CTTTATCT HOX11 -2200/-2193 CGTTAGG
c-Myb -792/-784 CAACTGCC RARγ -2225/-2217 GGCTCACC
C/EBP -798/-792 TTGCTC AIRE -2555/-2545 ATGGTTATCT
GR -847/-838 CTGTTCTCT Oct1 -2744/-2733 TCACTTTGCAT
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* Experimentally confirmed binding sites, C/EBP; CCAAT enhancer binding protein, NRF; NFκB repressing factor.

3.1. CCL2

CCL2 (MCP-1) is an important determinant of macrophage infiltration in ovarian tumors [92,93]. Although CCL2 has been originally thought to have an inhibitory effect on ovarian cancer progression [94,95,96], recent studies have indicated that CCL2 increases invasion of ovarian cancer cells and resistance to chemotherapy [97,98]. The putative transcription factor binding sites identified in human CCL2 promoter are listed in Table 2. Experimental studies demonstrated binding of NFκB, STAT1, STAT3, AP-1, and Hif-1α to the CCL2 promoter in OC cells (Figure 1).

Figure 1.

Figure 1

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Schematic illustration of human CCL2 promoter.

Even though the NFκB binding site is located in the distal regulatory region of human CCL2 promoter (Figure 1), several studies have demonstrated p65 NFκB involvement in the regulation of CCL2 expression in OC cells [27,41,99]. In addition, CCL2 expression is regulated by IKKβ-dependent recruitment of the transcription factor EGR-1, and inhibition of IKKβ activity decreases p65 and EGR-1 promoter recruitment and CCL2 expression [41]. Interestingly, the NFκB binding site in human CCL2 promoter has the same nucleotide sequence as the NFκB site in human IL-8/CXCL8 promoter. Curiously, both CCL2 and IL-8 are increased by paclitaxel [83] and bortezomib [41], indicating that the paclitaxel and BZ-induced CCL2 (and IL-8) increase is promoter specific.

Activity of the transcription factors STAT-1 and STAT-3 is also constitutively increased in OC cells, where it promotes cell motility and invasiveness [100]. Phosphorylation of STAT3 at tyrosine residues 705 and 727 increases its transcriptional activity [101]. In OC cells, IL-6 [102] and M-CSF [103] induce phosphorylation and activation of STAT3, and increase the CCL2 expression. In addition to NFκB and STAT transcription factors, studies in other cell types indicated that the CCL2 expression is positively regulated by AP-1 and Hif-1α [104,105,106,107].

Though no transcription factors have been reported to be involved in the negative regulation of CCL2 in OC cells, studies involving other cell types have reported negative regulators of CCL2. Specifically, NFκB p50/p50 homodimers, HDAC1, and the transcription factors Nrf2 and SMRT have been suggested to suppress the CCL2 expression in hepatic cells and adipocytes [108,109,110].

3.2. CXCL1

CXCL1 (GRO-α) contributes to ovarian cancer progression by inducing endothelial and epithelial cell proliferation and migration [25,26]. The putative transcription factor binding sites identified in human CXCL1 promoter are listed in Table 3. Experimental studies have demonstrated binding of the transcription factors p65 NFκB, AP-2, CCAAT displacement protein (CDP), and the stimulating protein-1 (SP-1) to the CXCL1 promoter in human cells (Figure 2). In ovarian cancer cells, though, the CXCL1 gene expression was found to be regulated mainly by NFκB pathway, specifically by the p65 DNA binding [25,27,28,111,112].

Figure 2.

Figure 2

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Schematic illustration of human CXCL1 promoter.

In addition to the positive regulation by p65 NFκB, AP-2 and SP-1, studies using human melanocytes have indicated that the CXCL1 expression is negatively controlled by the transcriptional repressors CDP and the poly(ADPribose) polymerase-1 (PARP-1) [113,114]. The exact mechanisms of how CDP and PARP-1 inhibit the CXCL1 expression are not fully understood; however, they likely involve displacement of trans-activating factors that bind to CXCL1 promoter, resulting in transcriptional repression.

3.3. CXCL2

The putative transcription factor binding sites identified in human CXCL2 (GRO-β) promoter are listed in Table 4. However, experimental studies have demonstrated only binding of NFκB, AP-1, and STAT3 to human CXCL2 promoter (Figure 3). In ovarian cancer cells, the CXCL2 expression is dependent on IκBα [28] and IKKβ [44]. In addition, the CXCL2 expression in OC cells is induced by TNF, and is inhibited by overexpression of the tumor suppressor p53 [115].

Figure 3.

Figure 3

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Schematic illustration of human CXCL2 promoter.

3.4. CXCL8

CXCL8 (IL-8), an inflammatory chemokine originally discovered as the neutrophil chemoattractant and inducer of leukocyte-mediated inflammation [1,2,3], contributes to cancer progression through its induction of tumor cell proliferation, migration and angiogenesis [4,5,6,7,8,9]. The expression levels of IL-8 directly correlate with ovarian cancer progression, and suppression of IL-8 expression inhibits angiogenesis and tumorigenicity of ovarian cancer cells [13,116,117,118]. A number of studies have identified a minimal region in human IL-8 promoter that spans nucleotides -1 to -140, is necessary for IL-8 transcription, and contains binding sites for NFκB, AP-1, CCAAT enhancer-binding protein beta (C/EBP or NF-IL6), Hif-1, and NFκB-repressing factor (NRF) [119,120,121,122,123,124,125,126,127]. In addition, the IL-8 transcription in ovarian cancer cells is positively regulated by the transcription factor early growth response-1 (EGR-1) binding to IL-8 promoter, and by enzymes of IKK complex that phosphorylate both IκBα, leading to its cytoplasmic degradation, and p65 NFκB, resulting in its increased transcriptional activity (Figure 4) [41,42,43,44,45].

Figure 4.

Figure 4

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Human CXCL8 promoter with the identified transcription factor binding sites.

NFκB is crucial for the IL-8 expression, and regulates IL-8 in all cell types [128]. The NFκB binding sequence (GGAATTTCC) is located between -80 and -70 of the IL-8 gene [120]. In most cell types, the IL-8 transcription is regulated predominantly by p65 homodimers [37,121,129,130,131]. Phosphorylation of p65 NFκB on serines 276 and 536 increases its transcriptional activity and interaction with other transcription factor and regulators, and decreases its affinity for nuclear IκBα [129,130,131,132,133]. We have recently shown that in ovarian cancer cells, the IL-8 transcription is regulated by S536-p65 NFκB, IKKβ, and EGR-1, and that proteasome inhibition developed as a strategy to inhibit NFκB-dependent transcription, paradoxically increases the IL-8 expression in ovarian cancer cells by increasing the S536-p65, IKKβ and EGR-1 recruitment to IL-8 promoter [41].

Adjacent to the NFκB site in the IL-8 promoter are C/EBP and Hif-1 binding sites (Figure 4). Even though the direct involvement of C/EBP and Hif-1 in the IL-8 regulation in ovarian cancer cells has yet to be demonstrated, the up-regulation of IL-8 expression by hypoxia in ovarian cancer cells has been well documented [30,134].

Transcription of IL-8 is also regulated by the transcription factor AP-1 that consists of Fos, FosB, Jun, and Jun-B subunits. Activation of AP-1 mediates the increased IL-8 expression in hypoxia, paclitaxel, and lysophosphatidic acid (LPA) treated OC cells [30,80,135]. Interestingly, a recent study has shown that the stress hormones norepinephrine and epinephrine enhance the IL-8 expression by a FosB-dependent mechanism [136]. Table 5 lists all putative transcription factor binding sites identified in the human CXCL8/IL-8 promoter.

Although studies from other cell types have shown that the IL-8 expression is negatively regulated by the NFκB repressing factor NRF, nuclear receptor corepressor (NCoR), the silencing mediator for retinoic acid and thyroid hormone receptor SMRT, and HDACs [54,137,138,139], the potential involvement of these corepressors in OC cells has yet to be demonstrated. Considering the important role these corepressors play in the IL-8 regulation, it will be important to elucidate their function in ovarian cancer setting.

4. Conclusions and Perspectives

As we continue to improve our understanding of the mechanisms regulating chemokine expression in ovarian cancer cells, our knowledge will contribute to the development of new therapeutic strategies targeting the increased chemokine expression in chemoresistant metastatic ovarian cancer. Several important questions remain to be answered: What are the specific molecular targets and mechanisms responsible for the chemokine expression induced by chemotherapeutic drugs and hypoxia? What is the role of HDACs and other transcriptional repressors in regulating the chemokine expression in ovarian cancer cells? What is the role of the metabolic state of ovarian cancer cells in regulating the chemokine expression? Answers to these questions may open new avenues for therapeutic approaches for treating ovarian cancer.

Acknowledgments

We apologize to any scientists whose work could not be cited in this review due to space limitations; Work in the Vancurova lab is supported by grant CA173452 from the National Institutes of Health.

Author Contributions

All authors have contributed to the drafting, writing and critical revision of the manuscript, and have approved the final version of the manuscript.

Conflicts of Interest

The authors declare no conflicts of interest.

References

  • 1.Baggiolini M., Walz A., Kunkel S.L. Neutrophil-activating peptide-1/interleukin 8, a novel cytokine that activates neutrophils. J. Clin. Investig. 1989;84:1045–1049. doi: 10.1172/JCI114265. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 2.Kunkel S.L., Strieter R.M., Chensue S.W., Basha M., Standiford T., Ham J., Remick D.G. Tumor necrosis factor-alpha, interleukin-8 and chemotactic cytokines. Prog. Clin. Biol. Res. 1990;349:433–444. [PubMed] [Google Scholar]
  • 3.Baggiolini M., Dewald B., Moser B. Human chemokines: An update. Annu. Rev. Immunol. 1997;15:675–705. doi: 10.1146/annurev.immunol.15.1.675. [DOI] [PubMed] [Google Scholar]
  • 4.Murphy P.M. Chemokines and the molecular basis of cancer metastasis. N. Engl. J. Med. 2001;345:833–835. doi: 10.1056/NEJM200109133451113. [DOI] [PubMed] [Google Scholar]
  • 5.Balkwill F., Mantovani A. Inflammation and cancer: Back to Virchow? Lancet. 2001;357:539–545. doi: 10.1016/S0140-6736(00)04046-0. [DOI] [PubMed] [Google Scholar]
  • 6.Zlotnik A. Chemokines and cancer. Int. J. Cancer. 2006;119:2026–2029. doi: 10.1002/ijc.22024. [DOI] [PubMed] [Google Scholar]
  • 7.Mantovani A., Allavena P., Sica A., Balkwill F. Cancer-related inflammation. Nature. 2008;454:436–444. doi: 10.1038/nature07205. [DOI] [PubMed] [Google Scholar]
  • 8.Lazennec G., Richmond A. Chemokines and chemokine receptors: New insights into cancer-related inflammation. Trends Mol. Med. 2010;16:133–144. doi: 10.1016/j.molmed.2010.01.003. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 9.Rainczuk A., Rao J., Gathercole J., Stephens A.N. The emerging role of CXC chemokines in epithelial ovarian cancer. Reproduction. 2012;144:303–317. doi: 10.1530/REP-12-0153. [DOI] [PubMed] [Google Scholar]
  • 10.Zlotnik A., Yoshie O. Chemokines: A new classification system and their role in immunity. Immunity. 2000;12:121–127. doi: 10.1016/S1074-7613(00)80165-X. [DOI] [PubMed] [Google Scholar]
  • 11.Fernandez E.J., Lolis E. Structure, function, and inhibition of chemokines. Annu. Rev. Pharmacol. Toxicol. 2002;42:469–499. doi: 10.1146/annurev.pharmtox.42.091901.115838. [DOI] [PubMed] [Google Scholar]
  • 12.Zlotnik A., Yoshie O. The chemokine superfamily revisited. Immunity. 2012;36:705–716. doi: 10.1016/j.immuni.2012.05.008. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 13.Xu L., Fidler I.J. Interleukin 8: An autocrine growth factor for human ovarian cancer. Oncol. Res. 2000;12:97–106. doi: 10.3727/096504001108747567. [DOI] [PubMed] [Google Scholar]
  • 14.Szlosarek P., Balkwill F. The inflammatory cytokine network of epithelial cancer: Therapeutic implications. Novartis Found. Symp. 2004;256:227–237. [PubMed] [Google Scholar]
  • 15.Waugh D.J., Wilson C. The interleukin-8 pathway in cancer. Clin. Cancer Res. 2008;14:6735–6741. doi: 10.1158/1078-0432.CCR-07-4843. [DOI] [PubMed] [Google Scholar]
  • 16.Sarvaiya P.J., Guo D., Ulasov I., Gabikian P., Lesniak M.S. Chemokines in tumor progression and metastasis. Oncotarget. 2013;4:2171–2185. doi: 10.18632/oncotarget.1426. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 17.Muralidhar G.G., Barbolina M.V. Chemokine receptors in epithelial ovarian cancer. Int. J. Mol. Sci. 2013;15:361–376. doi: 10.3390/ijms15010361. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 18.Negus R.P., Stamp G.W., Relf M.G., Burke F., Malik S.T., Bernasconi S., Allavena P., Sozzani S., Mantovani A., Balkwill F.R. The detection and localization of monocyte chemoattractant protein-1 (MCP-1) in human ovarian cancer. J. Clin. Investig. 1995;95:2391–2396. doi: 10.1172/JCI117933. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 19.Milliken D., Scotton C., Raju S., Balkwill F., Wilson J. Analysis of chemokines and chemokine receptor expression in ovarian cancer ascites. Clin. Cancer Res. 2002;8:1108–1114. [PubMed] [Google Scholar]
  • 20.Negus R.P., Stamp G.W., Hadley J., Balkwill F.R. Quantitative assessment of the leukocyte infiltrate in ovarian cancer and its relationship to the expression of C-C chemokines. Am. J. Pathol. 1997;150:1723–1734. [PMC free article] [PubMed] [Google Scholar]
  • 21.Levina V., Nolen B.M., Marrangoni A.M., Cheng P., Marks J.R., Szczepanski M.J., Szajnik M.E., Gorelik E., Lokshin A.E. Role of eotaxin-1 signaling in ovarian cancer. Clin. Cancer Res. 2009;15:2647–2656. doi: 10.1158/1078-0432.CCR-08-2024. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 22.Nolen B.M., Lokshin A.E. Targeting CCL11 in the treatment of ovarian cancer. Expert Opin. Ther. Target. 2010;14:157–167. doi: 10.1517/14728220903512983. [DOI] [PubMed] [Google Scholar]
  • 23.Singh R., Stockard C.R., Grizzle W.E., Lillard J.W., Jr., Singh S. Expression and histopathological correlation of CCR9 and CCL25 in ovarian cancer. Int. J. Oncol. 2011;39:373–381. doi: 10.3892/ijo.2011.1059. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 24.Facciabene A., Peng X., Hagemann I.S., Balint K., Barchetti A., Wang L., Gimotty P.A., Gilks C.B., Lal P., Zhang L. Tumour hypoxia promotes tolerance and angiogenesis via CCL28 and Treg cells. Nature. 2011;475:226–230. doi: 10.1038/nature10169. [DOI] [PubMed] [Google Scholar]
  • 25.Lee Z., Swaby R.F., Liang Y., Yu S., Liu S., Lu K.H., Bast R.C., Jr., Mills G.B., Fang X. Lysophosphatidic acid is a major regulator of growth-regulated oncogene alpha in ovarian cancer. Cancer Res. 2006;66:2740–2748. doi: 10.1158/0008-5472.CAN-05-2947. [DOI] [PubMed] [Google Scholar]
  • 26.Yang G., Rosen D.G., Zhang Z., Bast R.C., Jr., Mills G.B., Colacino J.A., Mercado-Uribe I., Liu J. The chemokine growth-regulated oncogene 1 (Gro-1) links RAS signaling to the senescence of stromal fibroblasts and ovarian tumorigenesis. Proc. Natl. Acad. Sci. USA. 2006;103:16472–16477. doi: 10.1073/pnas.0605752103. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 27.Son D., Parl A.K., Rice V.M., Khabele D. Keratinocyte chemoattractant (KC)/human growth-regulated oncogene (GRO) chemokines and pro-inflammatory chemokine networks in mouse and human ovarian epithelial cancer cells. Cancer Biol. Ther. 2007;6:1302–1312. doi: 10.4161/cbt.6.8.4506. [DOI] [PubMed] [Google Scholar]
  • 28.Kavandi L., Collier M.A., Nguyen H., Syed V. Progesterone and calcitriol attenuate inflammatory cytokines CXCL1 and CXCL2 in ovarian and endometrial cancer cells. J. Cell Biochem. 2012;113:3143–3152. doi: 10.1002/jcb.24191. [DOI] [PubMed] [Google Scholar]
  • 29.Lee L.F., Schuerer-Maly C.C., Lofquist A.K., van Haaften-Day C., Ting J.P., White C.M., Martin B.K., Haskill J.S. Taxol-dependent transcriptional activation of IL-8 expression in a subset of human ovarian cancer. Cancer Res. 1996;56:1303–1308. [PubMed] [Google Scholar]
  • 30.Xu L., Xie K., Mukaida N., Matsushima K., Fidler I.J. Hypoxia-induced elevation in interleukin-8 expression by human ovarian carcinoma cells. Cancer Res. 1999;59:5822–5829. [PubMed] [Google Scholar]
  • 31.Zou W., Machelon V., Coulomb-L’Hermin A., Borvak J., Nome F., Isaeva T., Wei S., Krzysiek R., Durand-Gasselin I., Gordon A., et al. Stromal-derived factor-1 in human tumors recruits and alters the function of plasmacytoid precursor dendritic cells. Nat. Med. 2001;7:1339–1346. doi: 10.1038/nm1201-1339. [DOI] [PubMed] [Google Scholar]
  • 32.Scotton C.J., Wilson J.L., Scott K., Stamp G., Wilbanks G.D., Fricker S., Bridger G., Balkwill F.R. Multiple actions of the chemokine CXCL12 on epithelial tumor cells in human ovarian cancer. Cancer Res. 2002;62:5930–5938. [PubMed] [Google Scholar]
  • 33.Guo L., Cui Z.M., Zhang J., Huang Y. Chemokine axes CXCL12/CXCR4 and CXCL16/CXCR6 correlate with lymph node metastasis in epithelial ovarian carcinoma. Chin. J. Cancer. 2011;30:336–343. doi: 10.5732/cjc.010.10490. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 34.Gooden M.J., Wiersma V.R., Boerma A., Leffers N., Boezen H.M., ten Hoor K.A., Hollema H., Walenkamp A.M., Daemen T., Nijman H.W., et al. Elevated serum CXCL16 is an independent predictor of poor survival in ovarian cancer and may reflect pro-metastatic ADAM protease activity. Br. J. Cancer. 2014;110:1535–1544. doi: 10.1038/bjc.2014.55. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 35.Gaudin F., Nasreddine S., Donnadieu A.C., Emilie D., Combadière C., Prévot S., Machelon V., Balabanian K. Identification of the chemokine CX3CL1 as a new regulator of malignant cell proliferation in epithelial ovarian cancer. PLOS ONE. 2011;6:e21546. doi: 10.1371/journal.pone.0021546. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 36.Kim M., Rooper L., Xie J., Rayahin J., Burdette J.E., Kajdacsy-Balla A.A., Barbolina M.V. The lymphotactin receptor is expressed in epithelial ovarian carcinoma and contributes to cell migration and proliferation. Mol. Cancer Res. 2012;10:1419–1429. doi: 10.1158/1541-7786.MCR-12-0361. [DOI] [PubMed] [Google Scholar]
  • 37.Huang S., Robinson J.B., Deguzman A., Bucana C.D., Fidler I.J. Blockade of NFκB signaling inhibits angiogenesis and tumorigenicity of human ovarian cancer cells by suppressing expression of VEGF and IL-8. Cancer Res. 2000;60:5334–5339. [PubMed] [Google Scholar]
  • 38.Mabuchi S., Ohmichi M., Nishio Y., Hayasaka T., Kimura A., Ohta T., Kawagoe J., Takahashi K., Yada-Hashimoto N., Seino-Noda H., et al. Inhibition of NFκB increases the efficacy of cisplatin in in vitro and in vivo ovarian cancer models. J. Biol. Chem. 2004;279:23477–23485. doi: 10.1074/jbc.M313709200. [DOI] [PubMed] [Google Scholar]
  • 39.Annunziata C.M., Stavnes H.T., Kleinberg L., Berner A., Hernandez L.F., Birrer M.J., Steinberg S.M., Davidson B., Kohn E.C. NFκB transcription factors are coexpressed and convey a poor outcome in ovarian cancer. Cancer. 2010;116:3276–3284. doi: 10.1002/cncr.25190. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 40.Leizer A.L., Alvero A.B., Fu H.H., Holmberg J.C., Cheng Y., Silasi D., Rutherford T., Mor G. Regulation of inflammation by the NFκB pathway in ovarian cancer stem cells. Am. J. Reprod. Immunol. 2011;65:438–447. doi: 10.1111/j.1600-0897.2010.00914.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 41.Singha B., Gatla H.R., Manna S., Chang T.P., Sanacora S., Poltoratsky V., Vancura A., Vancurova I. Proteasome inhibition increases recruitment of IκB kinase β (IKKβ), S536P-p65, and transcription factor EGR1 to interleukin-8 (IL-8) promoter, resulting in increased IL-8 production in ovarian cancer cells. J. Biol. Chem. 2014;289:2687–2700. doi: 10.1074/jbc.M113.502641. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 42.Mabuchi S., Ohmichi M., Nishio Y., Hayasaka T., Kimura A., Ohta T., Kawagoe J., Takahashi K., Yada-Hashimoto N., Seino-Noda H., et al. Inhibition of inhibitor of NFκB phosphorylation increases the efficacy of paclitaxel in in vitro and in vivo ovarian cancer models. Clin. Cancer Res. 2004;10:7645–7654. doi: 10.1158/1078-0432.CCR-04-0958. [DOI] [PubMed] [Google Scholar]
  • 43.Chen R., Alvero A., Silasi D., Kelly M., Fest S., Visintin I., Leiser A., Schwartz P., Rutherford T., Mor G. Regulation of IKKβ by miR-199a affects NFκB activity in ovarian cancer cells. Oncogene. 2008;27:4712–4723. doi: 10.1038/onc.2008.112. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 44.Hernandez L., Hsu S.C., Davidson B., Birrer M.J., Kohn E.C., Annunziata C.M. Activation of NFκB signaling by inhibitor of NFκB kinase beta increases aggressiveness of ovarian cancer. Cancer Res. 2010;70:4005–4014. doi: 10.1158/0008-5472.CAN-09-3912. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 45.Hsu S., Kim M., Hernandez L., Grajales V., Noonan A., Anver M., Davidson B., Annunziata C.M. IKK-ε coordinates invasion and metastasis of ovarian cancer. Cancer Res. 2012;72:5494–5504. doi: 10.1158/0008-5472.CAN-11-3993. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 46.Hayden M.S., Ghosh S. Shared principles in NFκB signaling. Cell. 2008;132:344–362. doi: 10.1016/j.cell.2008.01.020. [DOI] [PubMed] [Google Scholar]
  • 47.Smale S.T. Dimer-specific regulatory mechanisms within the NFκB family of transcription factors. Immunol. Rev. 2012;246:193–204. doi: 10.1111/j.1600-065X.2011.01091.x. [DOI] [PubMed] [Google Scholar]
  • 48.Natoli G. NFκB and chromatin: Ten years on the path from basic mechanisms to candidate drugs. Immunol. Rev. 2012;246:183–92. doi: 10.1111/j.1600-065X.2012.01103.x. [DOI] [PubMed] [Google Scholar]
  • 49.Strait K.A., Warnick C.T., Ford C.D., Dabbas B., Hammond E.H., Ilstrup S.J. Histone deacetylase inhibitors induce G2-checkpoint arrest and apoptosis in cisplatinum-resistant ovarian cancer cells associated with overexpression of the Bcl-2-related protein Bad. Mol. Cancer Ther. 2005;4:603–611. doi: 10.1158/1535-7163.MCT-04-0107. [DOI] [PubMed] [Google Scholar]
  • 50.Wilson A.J., Holson E., Wagner F., Zhang Y., Fass D.M., Haggarty S.J., Bhaskara S., Hiebert S.W., Schreiber S.L., Khabele D. The DNA damage mark pH2AX differentiates the cytotoxic effects of small molecule HDAC inhibitors in ovarian cancer cells. Cancer Biol. Ther. 2011;12:484–493. doi: 10.4161/cbt.12.6.15956. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 51.Singh B.N., Zhou H., Li J., Tipton T., Wang B., Shao G., Gilbert E.N., Li Q., Jiang S. Preclinical studies on histone deacetylase inhibitors as therapeutic reagents for endometrial and ovarian cancers. Future Oncol. 2011;7:1415–1428. doi: 10.2217/fon.11.124. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 52.Khabele D. The therapeutic potential of class I selective histone deacetylase inhibitors in ovarian cancer. Front. Oncol. 2014 doi: 10.3389/fonc.2014.00111. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 53.Ashburner B.P., Westerheide S.D., Baldwin A.S., Jr. The p65 (RelA) subunit of NFκB interacts with the histone deacetylase (HDAC) corepressors HDAC1 and HDAC2 to negatively regulate gene expression. Mol. Cell Biol. 2001;21:7065–7077. doi: 10.1128/MCB.21.20.7065-7077.2001. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 54.Rahman I., Gilmour P.S., Jimenez L.A., MacNee W. Oxidative stress and TNFα induce histone acetylation and NFκB/AP-1 activation in alveolar epithelial cells: Potential mechanism in gene transcription in lung inflammation. Mol. Cell Biochem. 2002;234–235:239–248. [PubMed] [Google Scholar]
  • 55.Tomita K., Barnes P., Adcock I. The effect of oxidative stress on histone acetylation and IL-8 release. Biochem. Biophys. Res. Commun. 2003;301:572–577. doi: 10.1016/S0006-291X(02)03029-2. [DOI] [PubMed] [Google Scholar]
  • 56.Mayo M.W., Denlinger C.E., Broad R.M., Yeung F., Reilly E.T., Shi Y., Jones D.R. Ineffectiveness of histone deacetylase inhibitors to induce apoptosis involves the transcriptional activation of NFκB through the Akt pathway. J. Biol. Chem. 2003;278:18980–18989. doi: 10.1074/jbc.M211695200. [DOI] [PubMed] [Google Scholar]
  • 57.Yang S.R., Chida A.S., Bauter M.R., Shafiq N., Seweryniak K., Maggirwar S.B., Kilty I., Rahman I. Cigarette smoke induces proinflammatory cytokine release by activation of NFκB and posttranslational modifications of histone deacetylase in macrophages. Am. J. Physiol. Lung Cell Mol. Physiol. 2006;291:L46–L57. doi: 10.1152/ajplung.00241.2005. [DOI] [PubMed] [Google Scholar]
  • 58.Ziesche E., Kettner-Buhrow D., Weber A., Wittwer T., Jurida L., Soelch J., Muller H., Newel D., Kronich P., Schneider H., et al. The coactivator role of histone deacetylase 3 in IL-1-signaling involves deacetylation of p65 NFκB. Nucl. Acids Res. 2013;41:90–109. doi: 10.1093/nar/gks916. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 59.Kim K.S., Sengupta S., Berk M., Kwak Y.G., Escobar P.F., Belinson J., Mok S.C., Xu Y. Hypoxia enhances lysophosphatidic acid responsiveness in ovarian cancer cells and lysophosphatidic acid induces ovarian tumor metastasis in vivo. Cancer Res. 2006;66:7983–7990. doi: 10.1158/0008-5472.CAN-05-4381. [DOI] [PubMed] [Google Scholar]
  • 60.Zhong H., de Marzo A.M., Laughner E., Lim M., Hilton D.A., Zagzag D., Buechler P., Isaacs W.B., Semenza G.L., Simons J.W. Overexpression of hypoxia-inducible factor 1α in common human cancers and their metastases. Cancer Res. 1999;59:5830–5835. [PubMed] [Google Scholar]
  • 61.Birner P., Schindl M., Obermair A., Breitenecker G., Oberhuber G. Expression of hypoxia-inducible factor 1α in epithelial ovarian tumors: Its impact on prognosis and on response to chemotherapy. Clin. Cancer Res. 2001;7:1661–1668. [PubMed] [Google Scholar]
  • 62.Braicu E.I., Luketina H., Richter R., Castillo-Tong D.C., Lambrechts S., Mahner S., Concin N., Mentze M., Zeillinger R., Vergote I. HIF1α is an independent prognostic factor for overall survival in advanced primary epithelial ovarian cancer—A study of the OVCAD Consortium. Oncol. Targets Ther. 2014;7:1563–1569. doi: 10.2147/OTT.S65373. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 63.Kryczek I., Lange A., Mottram P., Alvarez X., Cheng P., Hogan M., Moons L., Wei S., Zou L., Machelon V., et al. CXCL12 and vascular endothelial growth factor synergistically induce neoangiogenesis in human ovarian cancers. Cancer Res. 2005;65:465–472. [PubMed] [Google Scholar]
  • 64.Koong A.C., Chen E.Y., Giaccia A.J. Hypoxia causes the activation of NFκB through the phosphorylation of IκBα on tyrosine residues. Cancer Res. 1994;54:1425–1430. [PubMed] [Google Scholar]
  • 65.Culver C., Sundqvist A., Mudie S., Melvin A., Xirodimas D., Rocha S. Mechanism of hypoxia-induced NFκB. Mol. Cell Biol. 2010;30:4901–4921. doi: 10.1128/MCB.00409-10. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 66.Kim K.S., Rajagopal V., Gonsalves C., Johnson C., Kalra V.K. A novel role of hypoxia-inducible factor in cobalt chloride- and hypoxia-mediated expression of IL-8 chemokine in human endothelial cells. J. Immunol. 2006;177:7211–7224. doi: 10.4049/jimmunol.177.10.7211. [DOI] [PubMed] [Google Scholar]
  • 67.Kroemer G., Pouyssegur J. Tumor cell metabolism: Cancer’s Achilles’ heel. Cancer Cell. 2008;13:472–482. doi: 10.1016/j.ccr.2008.05.005. [DOI] [PubMed] [Google Scholar]
  • 68.Hsu P.P., Sabatini D.M. Cancer cell metabolism: Warburg and beyond. Cell. 2008;134:703–707. doi: 10.1016/j.cell.2008.08.021. [DOI] [PubMed] [Google Scholar]
  • 69.Semenza G.L. HIF-1 mediates metabolic responses to intratumoral hypoxia and oncogenic mutations. J. Clin. Investig. 2013;123:3664–3671. doi: 10.1172/JCI67230. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 70.Xu L., Fidler I.J. Acidic pH-induced elevation in interleukin 8 expression by human ovarian carcinoma cells. Cancer Res. 2000;60:4610–4616. [PubMed] [Google Scholar]
  • 71.Vegran F., Boidot R., Michiels C., Sonveaux P., Feron O. Lactate influx through the endothelial cell monocarboxylate transporter MCT1 supports an NFκB/IL-8 pathway that drives tumor angiogenesis. Cancer Res. 2011;71:2550–2560. doi: 10.1158/0008-5472.CAN-10-2828. [DOI] [PubMed] [Google Scholar]
  • 72.Anderson A.S., Roberts P.C., Frisard M.I., McMillan R.P., Brown T.J., Lawless M.H., Hulver M.W., Schmelz E.M. Metabolic changes during ovarian cancer progression as targets for sphingosine treatment. Exp. Cell Res. 2013;319:1431–1442. doi: 10.1016/j.yexcr.2013.02.017. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 73.Caneba C., Yang L., Baddour J., Curtis R., Win J., Hartig S., Marini J., Nagrath D. Nitric oxide is a positive regulator of the Warburg effect in ovarian cancer cells. Cell Death Dis. 2014;5:e1302. doi: 10.1038/cddis.2014.264. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 74.Kellenberger L.D., Bruin J.E., Greenaway J., Campbell N.E., Moorehead R.A., Holloway A.C., Petrik J. The role of dysregulated glucose metabolism in epithelial ovarian cancer. J. Oncol. 2010 doi: 10.1155/2010/514310. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 75.Gallagher E.J., LeRoith D. Diabetes, cancer, and metformin: Connections of metabolism and cell proliferation. Ann. NY Acad. Sci. 2011;1243:54–68. doi: 10.1111/j.1749-6632.2011.06285.x. [DOI] [PubMed] [Google Scholar]
  • 76.Hursting S.D., Dunlap S.M., Ford N.A., Hursting M.J., Lashinger L.M. Calorie restriction and cancer prevention: A mechanistic perspective. Cancer Metable. 2013 doi: 10.1186/2049-3002-1-10. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 77.Al-Wahab Z., Tebbe C., Chhina J., Dar S.A., Morris R.T., Ali-Fehmi R., Giri S., Munkarah A.R., Rattan R. Dietary energy balance modulates ovarian cancer progression and metastasis. Oncotarget. 2014;5:6063–6075. doi: 10.18632/oncotarget.2168. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 78.Shimazu T., Hirschey M.D., Newman J., He W., Shirakawa K., le Moan N., Grueter C.A., Lim H., Saunders L.R., Stevens R.D., et al. Suppression of oxidative stress by β-hydroxybutyrate, an endogenous histone deacetylase inhibitor. Science. 2013;339:211–214. doi: 10.1126/science.1227166. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 79.De Visser K.E., Jonkers J. Towards understanding the role of cancer-associated inflammation in chemoresistance. Curr. Pharm. Des. 2009;15:1844–1853. doi: 10.2174/138161209788453239. [DOI] [PubMed] [Google Scholar]
  • 80.Lee L.F., Haskill J.S., Mukaida N., Matsushima K., Ting J.P. Identification of tumor-specific paclitaxel (Taxol)-responsive regulatory elements in theinterleukin-8 promoter. Mol. Cell Biol. 1997;17:5097–5105. doi: 10.1128/mcb.17.9.5097. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 81.Aghajanian C. Clinical update: Novel targets in gynecologic malignancies. Semin. Oncol. 2004;31:22–26. doi: 10.1053/j.seminoncol.2004.10.015. [DOI] [PubMed] [Google Scholar]
  • 82.Kelly M.G., Alvero A.B., Chen R., Silasi D.A., Abrahams V.M., Chan S., Visintin I., Rutherford T., Mor G. TLR-4 signaling promotes tumor growth and paclitaxel chemoresistance in ovarian cancer. Cancer Res. 2006;66:3859–3868. doi: 10.1158/0008-5472.CAN-05-3948. [DOI] [PubMed] [Google Scholar]
  • 83.Szajnik M., Szczepanski M.J., Czystowska M., Elishaev E., Mandapathil M., Nowak-Markwitz E., Spaczynski M., Whiteside T.L. TLR4 signaling induced by lipopolysaccharide or paclitaxel regulates tumor survival and chemoresistance in ovarian cancer. Oncogene. 2009;28:4353–4363. doi: 10.1038/onc.2009.289. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 84.Frankel A., Man S., Elliott P., Adams J., Kerbel R.S. Lack of multicellular drug resistance observed in human ovarian and prostate carcinoma treated with the proteasome inhibitor PS-341. Clin. Cancer Res. 2000;6:3719–3728. [PubMed] [Google Scholar]
  • 85.Aghajanian C., Dizon D.S., Sabbatini P., Raizer J.J., Dupont J., Spriggs D.R. Phase I trial of bortezomib and carboplatin in recurrent ovarian or primary peritoneal cancer. J. Clin. Oncol. 2005;23:5943–5949. doi: 10.1200/JCO.2005.16.006. [DOI] [PubMed] [Google Scholar]
  • 86.Ramirez P.T., Landen C.N., Jr., Coleman R.L., Milam M.R., Levenback C., Johnston T.A., Gershenson D.M. Phase I trial of the proteasome inhibitor bortezomib in combination with carboplatin in patients with platinum- and taxane-resistant ovarian cancer. Gynecol. Oncol. 2008;108:68–71. doi: 10.1016/j.ygyno.2007.08.071. [DOI] [PubMed] [Google Scholar]
  • 87.Aghajanian C., Blessing J.A., Darcy K.M., Reid G., deGeest K., Rubin S.C., Mannel R.S., Rotmensch J., Schilder R.J., Riordan W. A phase II evaluation of bortezomib in the treatment of recurrent platinum-sensitive ovarian or primary peritoneal cancer: A Gynecologic Oncology Group study. Gynecol. Oncol. 2009;115:215–220. doi: 10.1016/j.ygyno.2009.07.023. [DOI] [PubMed] [Google Scholar]
  • 88.Jandial D.D., Farshchi-Heydari S., Larson C.A., Elliott G.I., Wrasidlo W.J., Howell S.B. Enhanced delivery of cisplatin to intraperitoneal ovarian carcinomas mediated by the effects of bortezomib on the human copper transporter 1. Clin. Cancer Res. 2009;15:553–560. doi: 10.1158/1078-0432.CCR-08-2081. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 89.Howell S.B., Safaei R., Larson C.A., Sailor M.J. Copper transporters and the cellular pharmacology of the platinum-containing cancer drugs. Mol. Pharmacol. 2010;77:887–894. doi: 10.1124/mol.109.063172. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 90.Messeguer X., Escudero R., Farre D., Nunez O., Martinez J., Alba M.M. PROMO: Detection of known transcription regulatory elements using species-tailored searches. Bioinformatics. 2002;18:333–334. doi: 10.1093/bioinformatics/18.2.333. [DOI] [PubMed] [Google Scholar]
  • 91.Farre D., Roset R., Huerta M., Adsuara J.E., Rosello L., Alba M.M., Messeguer X. Identification of patterns in biological sequences at the ALGGEN server: PROMO and MALGEN. Nucleic Acids Res. 2003;31:3651–3653. doi: 10.1093/nar/gkg605. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 92.Negus R.P., Turner L., Burke F., Balkwill F.R. Hypoxia down-regulates MCP-1 expression: Implications for macrophage distribution in tumors. J. Leukoc. Biol. 1998;63:758–765. doi: 10.1002/jlb.63.6.758. [DOI] [PubMed] [Google Scholar]
  • 93.Sica A., Saccani A., Bottazzi B., Bernasconi S., Allavena P., Gaetano B., Fei F., LaRosa G., Scotton C., Balkwill F., et al. Defective expression of the monocyte chemotactic protein-1 receptor CCR2 in macrophages associated with human ovarian carcinoma. J. Immunol. 2000;164:733–738. doi: 10.4049/jimmunol.164.2.733. [DOI] [PubMed] [Google Scholar]
  • 94.Wojnarowicz P., Gambaro K., de Ladurantaye M., Quinn M.C., Provencher D., Mes-Masson A.M., Tonin P.N. Overexpressing the CCL2 chemokine in an epithelial ovarian cancer cell line results in latency of in vivo tumourigenicity. Oncogenesis. 2012;1:e27. doi: 10.1038/oncsis.2012.25. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 95.Fader A.N., Rasool N., Vaziri S.A., Kozuki T., Faber P.W., Elson P., Biscotti C.V., Michener C.M., Rose P.G., Rojas-Espaillat L., et al. CCL2 expression in primary ovarian carcinoma is correlated with chemotherapy response and survival outcomes. Anticancer Res. 2010;12:4791–4798. [PubMed] [Google Scholar]
  • 96.Arnold J.M., Huggard P.R., Cummings M., Ramm G.A., Chenevix-Trench G. Reduced expression of chemokine (C-C motif) ligand-2 (CCL2) in ovarian adenocarcinoma. Br. J. Cancer. 2005;92:2024–2031. doi: 10.1038/sj.bjc.6602596. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 97.Moisan F., Francisco E.B., Brozovic A., Duran G.E., Wang Y.C., Chaturvedi S., Seetharam S., Snyder L.A., Doshi P., Sikic B.I. Enhancement of paclitaxel and carboplatin therapies by CCL2 blockade in ovarian cancers. Mol. Oncol. 2014;8:1231–1239. doi: 10.1016/j.molonc.2014.03.016. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 98.Furukawa S., Soeda S., Kiko Y., Suzuki O., Hashimoto Y., Watanabe T., Nishiyama H., Tasaki K., Hojo H., Abe M., et al. MCP-1 promotes invasion and adhesion of human ovarian cancer cells. Anticancer Res. 2013;33:4785–4790. [PubMed] [Google Scholar]
  • 99.Szlosarek P.W., Grimshaw M.J., Kulbe H., Wilson J.L., Wilbanks G.D., Burke F., Balkwill F.R. Expression and regulation of tumor necrosis factor alpha in normal and malignant ovarian epithelium. Mol. Cancer Ther. 2006;5:382–390. doi: 10.1158/1535-7163.MCT-05-0303. [DOI] [PubMed] [Google Scholar]
  • 100.Silver D.L., Naora H., Liu J., Cheng W., Montell D.J. Activated signal transducer and activator of transcription (STAT) 3: Localization in focal adhesions and function in ovarian cancer cell motility. Cancer Res. 2004;64:3550–3558. doi: 10.1158/0008-5472.CAN-03-3959. [DOI] [PubMed] [Google Scholar]
  • 101.Zhang X., Guo A., Yu J., Possemato A., Chen Y., Zheng W., Polakiewicz R.D., Kinzler K.W., Vogelstein B., Velculescu V.E., et al. Identification of STAT3 as a substrate of receptor protein tyrosine phosphatase T. Proc. Natl. Acad. Sci. USA. 2007;104:4060–4064. doi: 10.1073/pnas.0611665104. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 102.Coward J., Kulbe H., Chakravarty P., Leader D., Vassileva V., Leinster D.A., Thompson R., Schioppa T., Nemeth J., Vermeulen J., et al. Interleukin-6 as a therapeutic target in human ovarian cancer. Clin. Cancer Res. 2011;17:6083–6096. doi: 10.1158/1078-0432.CCR-11-0945. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 103.Takaishi K., Komohara Y., Tashiro H., Ohtake H., Nakagawa T., Katabuchi H., Takeya M. Involvement of M2-polarized macrophages in the ascites from advanced epithelial ovarian carcinoma in tumor progression via Stat3 activation. Cancer Sci. 2010;101:2128–2136. doi: 10.1111/j.1349-7006.2010.01652.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 104.Sutcliffe A.M., Clarke D.L., Bradbury D.A., Corbett L.M., Patel J.A., Knox A.J. Transcriptional regulation of monocyte chemotactic protein-1 release by endothelin-1 in human airway smooth muscle cells involves NFκB and AP-1. Br. J. Pharmacol. 2009;157:436–450. doi: 10.1111/j.1476-5381.2009.00143.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 105.Chen I.Y., Chang S.C., Wu H.Y., Yu T.C., Wei W.C., Lin S., Chien C.L., Chang M.F. Upregulation of the chemokine (C-C motif) ligand 2 via a severe acute respiratory syndrome coronavirus spike-ACE2 signaling pathway. J. Virol. 2010;84:7703–7712. doi: 10.1128/JVI.02560-09. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 106.Dragomir E., Manduteanu I., Calin M., Gan A.M., Stan D., Koenen R.R., Weber C., Simionescu M. High glucose conditions induce upregulation of fractalkine and monocyte chemotactic protein-1 in human smooth muscle cells. Thromb. Haemost. 2008;100:1155–1165. [PubMed] [Google Scholar]
  • 107.Mojsilovic-Petrovic J., Callaghan D., Cui H., Dean C., Stanimirovic D.B., Zhang W. Hypoxia-inducible factor-1 (HIF-1) is involved in the regulation of hypoxia-stimulated expression of monocyte chemoattractant protein-1 (MCP-1/CCL2) and MCP-5 (Ccl12) in astrocytes. J. Neuroinflam. 2007 doi: 10.1186/1742-2094-4-12. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 108.Elsharkawy A.M., Oakley F., Lin F., Packham G., Mann D.A., Mann J. The NFκB p50:p50:HDAC-1 repressor complex orchestrates transcriptional inhibition of multiple pro-inflammatory genes. J. Hepatol. 2010;53:519–527. doi: 10.1016/j.jhep.2010.03.025. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 109.Ichihara S., Yamada Y., Liu F., Murohara T., Itoh K., Yamamoto M., Ichihara G. Ablation of the transcription factor Nrf2 promotes ischemia-induced neovascularization by enhancing the inflammatory response. Arterioscler. Thromb. Vasc. Biol. 2010;30:1553–1561. doi: 10.1161/ATVBAHA.110.204123. [DOI] [PubMed] [Google Scholar]
  • 110.Toubal A., Clement K., Fan R., Ancel P., Pelloux V., Rouault C., Veyrie N., Hartemann A., Treuter E., Venteclef N. SMRT-GPS2 corepressor pathway dysregulation coincides with obesity-linked adipocyte inflammation. J. Clin. Investig. 2013;123:362–379. doi: 10.1172/JCI64052. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 111.Dong Y., Kabir S.M., Lee E., Son D. CXCR2-driven ovarian cancer progression involves upregulation of proinflammatory chemokines by potentiating NFκB Activation via EGFR-transactivated Akt signaling. PLOS ONE. 2013;8:e83789. doi: 10.1371/journal.pone.0083789. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 112.Son D.S., Kabir S.M., Dong Y., Lee E., Adunyah S.E. Characteristics of chemokine signatures elicited by EGF and TNF in ovarian cancer cells. J. Inflamm. 2013 doi: 10.1186/1476-9255-10-25. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 113.Nirodi C., Hart J., Dhawan P., Moon N.S., Nepveu A., Richmond A. The role of CDP in the negative regulation of CXCL1 gene expression. J. Biol. Chem. 2001;276:26122–26131. doi: 10.1074/jbc.M102872200. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 114.Amiri K., Ha H., Smulson M., Richmond A. Differential regulation of CXC ligand 1 transcription in melanoma cell lines by poly(ADP-ribose) polymerase-1. Oncogene. 2006;25:7714–7722. doi: 10.1038/sj.onc.1209751. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 115.Son D., Kabir S.M., Dong Y., Lee E., Adunyah S.E. Inhibitory effect of tumor suppressor p53 on proinflammatory chemokine expression in ovarian cancer cells by reducing proteasomal degradation of IκB. PLOS ONE. 2012;7:e51116. doi: 10.1371/journal.pone.0051116. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 116.Yoneda J., Kuniyasu H., Crispens M.A., Price J.E., Bucana C.D., Fidler I.J. Expression of angiogenesis-related genes and progression of human ovarian carcinomas in nude mice. J. Natl. Cancer Inst. 1998;90:447–454. doi: 10.1093/jnci/90.6.447. [DOI] [PubMed] [Google Scholar]
  • 117.Merritt W.M., Lin Y.G., Spannuth W.A., Fletcher M.S., Kamat A.A., Han L.Y., Landen C.N., Jennings N., de Geest K., Langley R.R., et al. Effect of interleukin-8 gene silencing with liposome-encapsulated small interfering RNA on ovarian cancer cell growth. J. Natl. Cancer Inst. 2008;100:359–372. doi: 10.1093/jnci/djn024. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 118.Pecot C.V., Rupaimoole R., Yang D., Akbani R., Ivan C., Lu C., Wu S., Han H., Shah M.Y., Rodriguez-Aguayo C., et al. Tumour angiogenesis regulation by the miR-200 family. Nat. Commun. 2013 doi: 10.1038/ncomms3427. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 119.Mukaida N., Shiroo M., Matsushima K. Genomic structure of the human monocyte-derived neutrophil chemotactic factor IL-8. J. Immunol. 1989;143:1366–1371. [PubMed] [Google Scholar]
  • 120.Mukaida N., Mahe Y., Matsushima K. Cooperative interaction of nuclear factor-kappa B- and cis-regulatory enhancer binding protein-like factor binding elements in activating the interleukin-8 gene by pro-inflammatory cytokines. J. Biol. Chem. 1990;265:21128–21133. [PubMed] [Google Scholar]
  • 121.Kunsch C., Rosen C.A. NFκB subunit-specific regulation of the interleukin-8 promoter. Mol. Cell Biol. 1993;13:6137–6146. doi: 10.1128/mcb.13.10.6137. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 122.Stein B., Baldwin A.S., Jr. Distinct mechanisms for regulation of the interleukin-8 gene involve synergism and cooperativity between C/EBP and NFκB. Mol. Cell Biol. 1993;13:7191–7198. doi: 10.1128/mcb.13.11.7191. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 123.Matsusaka T., Fujikawa K., Nishio Y., Mukaida N., Matsushima K., Kishimoto T., Akira S. Transcription factors NF-IL6 and NFκB synergistically activate transcription of the inflammatory cytokines, interleukin 6 and interleukin 8. Proc. Natl. Acad. Sci. USA. 1993;90:10193–10197. doi: 10.1073/pnas.90.21.10193. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 124.Kunsch C., Lang R.K., Rosen C.A., Shannon M.F. Synergistic transcriptional activation of the IL-8 gene by NFκB p65 (RelA) and NF-IL-6. J. Immunol. 1994;153:153–164. [PubMed] [Google Scholar]
  • 125.Oliveira I.C., Mukaida N., Matsushima K., Vilcek J. Transcriptional inhibition of the interleukin-8 gene by interferon is mediated by the NFκB site. Mol. Cell Biol. 1994;14:5300–5308. doi: 10.1128/mcb.14.8.5300. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 126.Yasumoto K., Okamoto S., Mukaida N., Murakami S., Mai M., Matsushima K. Tumor necrosis factor alpha and interferon gamma synergistically induce interleukin 8 production in a human gastric cancer cell line through acting concurrently on AP-1 and NFκB-like binding sites of the interleukin 8 gene. J. Biol. Chem. 1992;267:22506–22511. [PubMed] [Google Scholar]
  • 127.Nourbakhsh M., Kalble S., Dorrie A., Hauser H., Resch K., Kracht M. The NFκB repressing factor is involved in basal repression and interleukin (IL)-1-induced activation of IL-8 transcription by binding to a conserved NFκB-flanking sequence element. J. Biol. Chem. 2001;276:4501–4508. doi: 10.1074/jbc.M007532200. [DOI] [PubMed] [Google Scholar]
  • 128.Hoffmann E., Dittrich-Breiholz O., Holtmann H., Kracht M. Multiple control of interleukin-8 gene expression. J. Leukoc. Biol. 2002;72:847–855. [PubMed] [Google Scholar]
  • 129.Sasaki C.Y., Barberi T.J., Ghosh P., Longo D.L. Phosphorylation of RelA/p65 on serine 536 defines an IκBα -independent NFκB pathway. J. Biol. Chem. 2005;280:34538–34547. doi: 10.1074/jbc.M504943200. [DOI] [PubMed] [Google Scholar]
  • 130.Ghosh C.C., Ramaswami S., Juvekar A., Vu H.Y., Galdieri L., Davidson D., Vancurova I. Gene-specific repression of proinflammatory cytokines in stimulated human macrophages by nuclear IκBα. J. Immunol. 2010;185:3685–3693. doi: 10.4049/jimmunol.0902230. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 131.Manna S., Singha B., Phyo S.A., Gatla H.R., Chang T.P., Sanacora S., Ramaswami S., Vancurova I. Proteasome inhibition by bortezomib increases IL-8 expression in androgen-independent prostate cancer cells: The role of IKKα. J. Immunol. 2013;191:2837–2846. doi: 10.4049/jimmunol.1300895. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 132.Buss H., Dörrie A., Schmitz M.L., Hoffmann E., Resch K., Kracht M. Constitutive and IL-1-inducible phosphorylation of p65 NFκB at serine 536 is mediated by multiple protein kinases including IκB kinase (IKK)-α, IKKβ, IKKε, TRAF family member-associated (TANK)-binding kinase 1 (TBK1), and an unknown kinase and couples p65 to TATA-binding protein associated factor II31-mediated IL-8 transcription. J. Biol. Chem. 2004;279:55633–55643. doi: 10.1074/jbc.M409825200. [DOI] [PubMed] [Google Scholar]
  • 133.Moreno R., Sobotzik J.M., Schultz C., Schmitz M.L. Specification of the NFκB transcriptional response by p65 phosphorylation and TNF-induced nuclear translocation of IKK epsilon. Nucleic Acids Res. 2010;38:6029–6044. doi: 10.1093/nar/gkq439. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 134.Xu L., Pathak P.S., Fukumura D. Hypoxia-induced activation of p38 mitogen-activated protein kinase and phosphatidylinositol 3'-kinase signaling pathways contributes to expression of interleukin 8 in human ovarian carcinoma cells. Clin. Cancer Res. 2004;10:701–707. doi: 10.1158/1078-0432.CCR-0953-03. [DOI] [PubMed] [Google Scholar]
  • 135.Fang X., Yu S., Bast R.C., Liu S., Xu H.J., Hu S.X., LaPushin R., Claret F.X., Aggarwal B.B., Lu Y., et al. Mechanisms for lysophosphatidic acid-induced cytokine production in ovarian cancer cells. J. Biol. Chem. 2004;279:9653–9661. doi: 10.1074/jbc.M306662200. [DOI] [PubMed] [Google Scholar]
  • 136.Shahzad M.M., Arevalo J.M., Armaiz-Pena G.N., Lu C., Stone R.L., Moreno-Smith M., Nishimura M., Lee J.W., Jennings N.B., Bottsford-Miller J., et al. Stress effects on FosB- and IL8-driven ovarian cancer growth and metastasis. J. Biol. Chem. 2010;285:35462–35470. doi: 10.1074/jbc.M110.109579. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 137.Bartels M., Schweda A.T., Dreikhausen U., Frank R., Resch K., Beil W., Nourbakhsh M. Peptide-mediated disruption of NFκB/NRF interaction inhibits IL-8 gene activation by IL-1 or Helicobacter pylori. J. Immunol. 2007;179:7605–7613. doi: 10.4049/jimmunol.179.11.7605. [DOI] [PubMed] [Google Scholar]
  • 138.Hoberg J.E., Yeung F., Mayo M.W. SMRT derepression by the IκB kinase alpha: A prerequisite to NFκB transcription and survival. Mol. Cell. 2004;16:245–255. doi: 10.1016/j.molcel.2004.10.010. [DOI] [PubMed] [Google Scholar]
  • 139.Nozell S., Laver T., Patel K., Benveniste E.N. Mechanism of IFN-beta-mediated inhibition of IL-8 gene expression in astroglioma cells. J. Immunol. 2006;177:822–830. doi: 10.4049/jimmunol.177.2.822. [DOI] [PubMed] [Google Scholar]

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