Skip to main content
NCBI home page
Current Genomics logoLink to Current Genomics
. 2008 Sep;9(6):409–419. doi: 10.2174/138920208785699571

Expression and Function of Bcl-2 Proteins in Melanoma

Jürgen Eberle 1,*, Amir M Hossini 1
PMCID: PMC2691663  PMID: 19506730

Abstract

Bcl-2 proteins are critical regulators of mitochondrial membrane permeability and the proapoptotic mitochondrial pathway. The family encloses pro- and antiapoptotic factors encoded by over 15 genes, which frequently give rise to alternative splice products. Antiapoptotic, proapoptotic multidomain, and proapoptotic BH3-only proteins are characterized by the presence of at least one of four Bcl-2 homology domains (BH 1-4). Their expression and activities are controlled by survival pathways as MAP kinases and protein kinase B/Akt, which are in touch with a number of transcription factors. In melanoma, the mitochondrial apoptosis pathways and Bcl-2 proteins appear of particular importance for apoptosis resistance, which has been addressed in clinical trials applying antisense-Bcl-2. Overexpression or induction of proapoptotic Bcl-2 proteins as well as the use of small molecule mimetics for the proapoptotic BH3 domain are further promising strategies.

Key Words: Melanoma, apoptosis, Bcl-2 proteins.

INTRODUCTION

Cancer is a predominant cause of death worldwide, and its importance is even further increasing due to the generally extending life expectancy. Currently one in four deaths in the United States and in Europe attributes to cancer, and in an age range between 45–65, the proportion further increases up to 50% [1, 2]. This attributes to the fact that the treatment options for disseminated cancer are largely insufficient.

A notable example is malignant melanoma of the skin, which is characterized by an unbroken high mortality with median survival rates of only 8 months in its disseminated stage. Patients can be cured only by early and complete surgical excision of the primary tumor, whereas in disseminated disease systemic therapies as various chemotherapies, biotherapies or vaccination protocols so far were not able to improve the dismal prognosis [3-5].

Though different mechanisms may contribute to chemoresistance, defective apoptosis signaling may be the predominant cause in cancer [6, 7]. This corresponds to the fact that cancer therapies in general aim at the elimination of tumor cells through apoptotic processes. Bcl-2 proteins, which will be the topic of this review, are major players in the regulation of apoptosis, and melanoma will be used as an example for discussing therapeutic strategies for targeting Bcl-2 proteins.

INTRINSIC PATHWAYS TO APOPTOSIS

In contrast to necrosis as a kind of accidental cell death, apoptosis is an active and physiological process indispensable for normal tissue homeostasis, which acts as a counterbalance for cell proliferation [8]. Beyond this, it provides fundamental safeguard mechanisms in protection from cancer by eliminating altered and potentially harmful cells.

Different types of cellular damage as well as cellular dysregulation such as oncogene activation induce cell-intrinsic proapoptotic pathways. Highly active is the mitochondrial pathway characterized by a release of mitochondrial proapoptotic factors into the cytoplasm [9]. This step is critically controlled by the family of Bcl-2 proteins (Fig. 1).

Fig. (1). Bcl-2 proteins in the control of the mitochondrial apoptosis pathway.

Fig. (1). Bcl-2 proteins in the control of the mitochondrial apoptosis pathway.

Open in a new tab

Abbreviations: Cyt C, cytochrome C; IAPs, inhibitors of apoptosis proteins; tBid, truncated Bid; BH3-only, BH3-only proteins; AIF, apoptosis-inducing factor; EndoG, endonuclease G; Apaf-1, apoptosis-activating factor.

As a master regulator in apoptosis, the transcription factor p53 triggers intrinsic pathways. Levels of p53 are kept low in healthy cells due to its short half-life and degradation by the proteasome pathway. Here the ubiquitin ligase Hdm2 exerts an important function [10]. In response to DNA damage, hypoxia, oncogene activation or other intrinsic problems, p53 is stabilized by several possible modification steps such as phosphorylation by ATM (ataxia telangiectasia-mutated), ATR (ATM- and rad3-related) or checkpoint kinases (Chk1, Chk2) [11]. As a transcription factor, p53 drives the expression of various proteins including the cell cycle inhibitor p21, which results in a stop of cell division, thus providing time for DNA repair. In case of irreparable damage however, p53 triggers the transcription of proapoptotic factors as in particular proapoptotic Bcl-2 proteins such as Bax, Noxa, Puma, Bik/Nbk and Bid. Furthermore, cytosolic p53 may also directly interact with Bcl-2 family members to trigger mitochondrial apoptosis [12-14].

The family of pro- and antiapoptotic Bcl-2 proteins critically controls the permeability of organelles as the outer mitochondrial membrane [15]. Once a certain threshold of proapoptotic signals is exceeded, a rapid release of mitochondrial intermembrane factors is induced. Several factors exert characteristic proapoptotic functions when emerging in the cytoplasm, as reported for cytochrome C, endonuclease G, AIF (apoptosis-inducing factor), Smac/DIABLO (second mitochondria-derived activator of caspases/direct IAP-binding protein with low pI) and HtrA2/Omi [16].

Cytochrome C triggers the formation of the apoptosome, a multiprotein complex enclosing each seven copies of the adaptor protein Apaf-1 (apoptosis-activating factor), Cyt C and ATP [17]. It allows the binding and activation of initiator caspase-9, which sets up a subsequent caspase cascade starting with caspase-3. Caspases (Cysteine-dependent aspartate directed poteases) represent hallmarks in apoptosis. They are synthesized as inactive zymogens, and they activate each other through cleavage processes thus forming signal cascades. Proapoptotic caspases are divided up in initiator caspases (2, 8, 9 and 10) and effector caspases (3, 6, and 7) [18, 19].

Effector caspases themselves have hundreds of different cellular protein targets (death substrates), which are inactivated or activated upon cleavage [20]. Thus, CAD (caspase-activated DNase) in healthy cells is hold in check by binding to ICAD (inhibitor of CAD). In course of apoptosis, CAD is released by caspase-mediated cleavage of ICAD resulting in a cleavage of DNA between nucleosomes visible as a characteristic DNA ladder [21]. In parallel, the DNA repair enzyme PARP (poly ADP-ribose polymerase) is inactivated upon caspase cleavage ensuring that energy resources are reserved for apoptosis as well as that DNA repair does not occur simultaneously to DNA fragmentation [22]. The result of such changes is the complete reprogramming of the cell for apoptosis.

The proapoptotic potential of other mitochondrial factors is related to the family of inhibitor of apoptosis proteins (IAPs). Their function in apoptosis is to block caspase-9 and effector caspases, which is achieved by binding to their active sites and/or by ubiquitination and targeting caspase degradation. Both Smac/Diablo and HtrA2/Omi have been described to augment caspase activation by antagonizing IAP proteins [23, 24]. In contrast, the activities of AIF and endonuclease G appear as largely independent from caspase pathways. After translocation to the cytosol and to the nucleus, their proapoptotic contribution depends on an endogeneous DNAse activity (Endo G) or DNA interaction, chromatin condensation and recruitment of downstream nucleases in case of AIF [25].

Thus, the mitochondrial membrane appears as a place for integration of different pro- and antiapoptotic signals, where the decision about life and death is made. The release of proapoptotic proteins appears as the critical step, which depends on the equilibrium between pro- and antiapoptotic Bcl-2 proteins. Proapoptotic Bcl-2 proteins support the mitochondrial permeability while the antiapoptotic proteins try to block it.

STRUCTURE OF Bcl-2 PROTEINS AND GENOMIC ORGANIZATION

Bcl-2 proteins are master regulators of the mitochondrial pathway. More than twenty known proteins of the family (incl. alternative splice products) are categorized according to their function (anti or proapoptotic) and according to the presence of up to four Bcl-2 homology domains (BH1 – BH4). Most antiapoptotic proteins as Bcl-2 or Bcl-xL share all four domains, whereas proapoptotic proteins separate into and multidomain proteins (Bax, Bak and Bok), which share BH 1, 2, 3 BH3-only proteins, which have only BH3(Fig. 2). In addition there are other proteins, which do not fit in these categories.

Fig. (2). Bcl-2 family proteins.

Fig. (2). Bcl-2 family proteins.

Open in a new tab

The superfamily of Bcl-2 proteins encloses antiapoptotic factors, proapoptotic Bax-like factors and BH3-only proteins. The presense of up to four Bcl-2 homology domains (BH 1-4) as well as in some proteins the transmembrane domain (TM) is indicated.

As concerning the genomic organization of the more than 15 genes encoding for Bcl-2 proteins, most of them are located on different chromosomes. Clustering is seen only occasionally, i.e. Bax and Puma reside in 19q13, and Bcl-2 and Noxa are in 18q21 (Table 1).

Table 1.

Characteristics of Bcl-2 Proteins

Proteins Chr. Location 1 Splicing 2 Activation 3
Antiapoptotic
Bcl-2 18q21.3 2 Ph
Bcl-w 14q11.2 - q12 n.r.
Mcl-1 1q21 2
Bcl-xL 20pter-p12.1 5 Deph / Ph
Bfl-1 15q24.3 2
Proapoptotic
Bax 19q13.3 - q13.4 8 Deph / Ph / p53
Bak 6p21.3 n.r. Con
Bid 22q11.2 4 Cl / p53
Bad 11cen-q12.3 n.r. Deph
Nbk/Bik 22q13.2-q13.3 n.r. Ph / p53
Hrk 12q24.21 n.r.
Bim 2q12-q13 10 Ph
Bmf 15q14 n.r. Ph
Puma 19q13.3 - q13.4 2 p53
Noxa 18q21.32 n.r. p53
Open in a new tab
1

Chromosomal location of bcl-2 genes.

2

Reported numbers of alternative splice products. For several splice variants, there is no function so far identified, as for several splice variants of Bim and two splice variants of Bax. For several proteins the number of splice products has not been reported (n.r.).

3

Mechanisms for activation of Bcl-2 proteins: Ph, phosphorylation; Deph, dephosphorylation; Cl, cleavage; Con, conformational change; p53, transactivation by p53.

MODELS FOR EXPLAINING THE REGULATION OF APOPTOSIS BY Bcl-2 PROTEINS

Despite intensive research since the identification of Bcl-2 in 1984 by the t(14;18) translocation in acute B-cell leukaemia [26], the exact mechanism(s), how Bcl-2 proteins control mitochondrial permeability, remain partly elusive. Different models have been suggested. Accordingly, the multidomain proapoptotic proteins are in healthy cells in an inactive conformation and either cytosolic (Bax) or only loosely attached to mitochondria (Bak). Upon induction of apoptosis, they are activated, undergo conformational changes and integrate deeper into the outer mitochondrial membrane, to either form channels themselves or trigger opening of the permeability transition pore (PTP) [27, 28].

In contrast, several antiapoptotic Bcl-2 proteins are permanent constituents of the mitochondrial membrane, where they protect membrane integrity. They bind to multidomain proteins Bax and Bak and thus block their proapoptotic activity. Supporting the model, Bcl-2 or Bcl-xL have been shown to prevent Bax translocation and activation [29-31], and Bcl-xL and Mcl-1 have been shown to sequester Bak in mitochondria [32].

The BH3-only proteins are regarded as triggers in apoptosis control. They are transactivated or post-translationally activated by protein modifications in response to diverse apoptotic stimuli. Thus, Bid is activated by proteolytic cleavage through caspase-8 or granzyme B, Bad is activated upon dephosphorylation and Bim is released from cytoskeletal structures [33-35]. Upon activation, they bind to the antiapoptotic Bcl-2 proteins thus to neutralize their activity and leading to a freeing of Bax and Bak [36]. BH3 is required for the interaction and binds into a hydrophobic pocket formed by BH1, BH2 and BH3 of antiapoptotic Bcl-2 proteins, thus leading to their neutralization (Adams and Cory, 2007).

Some BH3-only proteins display selective binding to specific antiapoptotic Bcl-2 family members as Bad, which interacts with Bcl-2, Bcl-w and Bcl-xL but not with Mcl-1, or Noxa, which binds to Mcl-1 and Bfl-1 but not Bcl-2 and Bcl-xL. Others as Puma and Bim may be less selective and bind to all antiapoptotic Bcl-2 proteins [37]. Thus more than one BH3-only protein may be required for induction of apoptosis, as demonstrated in HeLa cells, where the release of Bak from Bcl-xL and Mcl-1 required activation of Bad and Noxa [38]. Antiapoptotic Bcl-2 family members were shown to sequester BH3-only proteins at the mitochondria. Thus tBid and Bad were found in complex with Bcl-2 and Bcl-xL [39], and Bim was found in complex with Mcl-1, which was disrupted upon induction of apoptosis [40, 41].

Alternative models suggests that BH3-only proteins may also directly interact with Bax and Bak for their activation [42], however fluorescence imaging could not demonstrate their co-localization [43]. Besides their control of apoptosis and besides their localization in mitochondria, Bcl-2 proteins are also located in the endoplasmatic reticulum (ER), where they are involved in diverse cellular processes, like calcium homeostasis, autophagy, the unfolded protein response and ER morphogenesis [44].

ALTERNATIVE SPLICING

Some members of the Bcl-2 family are regulated by alternative splicing. A prominent example is Bim, which occurres as a short (BimS), a long (BimL) and an extra long protein (BimEL). All three proteins promote apoptosis, but have distinct activities and distinct modes of regulation conferred by their interaction with other proteins [45]. Even further splice products of Bim have been reported with undetermined function. Also for Bax eight splice variants have been reported, which have partly different domain structures, of which 6 have been shown to exert proapoptotic functions [46].

Also several antiapoptotic Bcl-2 proteins are controlled by alternative splicing. Thus for Bcl-2, an alternative splice product of so far unknown function has been reported (Bcl-2β), which lacks the transmembrane domain and preferentially locates to the cytosol [47]. Also Bfl-1 has a short alternative splice variant (Bfl-1S), which localizes to the nucleus due to an intrinsic nuclear localization sequence. Also Bfl-1S revealed antiapoptotic activities, as determined in coexpression experiments with Bax [48].

Finally the bcl-x gene is expressed in at least five reported isoforms of different activities. While Bcl-xL (long), Bcl-xβ and Bcl-xES (extra short) are antiapoptotic [49-51], Bcl-xS (short) and Bcl-xAK (alternative killer) exert proapoptotic functions. Most interestingly, Bcl-xAK is the first proapoptotic Bcl-2 protein that lacks the BH3 domain [52], which so far has been regarded as indispensable for the proapoptotic function [36]. Thus even other ways of apoptosis regulation by Bcl-2 proteins have to be considered.

Alternative splicing of Bcl-2 protein mRNAs seems to be regulated by different stimuli, which strongly depended on the cell type investigated. Thus for the example of Bcl-x proteins, glucocorticoids and progestins may selectively trigger bcl-xL mRNA expression and influence the ratio between bcl-xL and bcl-xS [53]. In glioma cells, Bcl-xL levels were increased by TPA, whereas interleukin-6 or GM-CSF reduced the proportion of Bcl-xL in leukemia cells [54].

As a selecting factor, the RNA binding protein Sam68 has been described. Depletion of Sam68 by siRNA caused accumulation of antiapoptotic Bcl-xL, whereas Sam68 up-regulation increased the levels of Bcl-xS [55].

Bcl-2 PROTEINS AND MELANOMA APOPTOSIS RESISTANCE

The mitochrondrial apoptosis pathways appear of particular importance for melanoma and are activated in response to diverse stimuli also including death ligands [56-58]. Antiapoptotic proteins as Bcl-2, Bcl-xL and Mcl-1 are highly expressed [59-61], and a high Bcl-2/Bax ratio correlated with apoptosis resistance [62].

Regulation of the expression of Bcl-2 has been attributed to microphthalmia-associated transcription factor (MITF) [63], whereas Bcl-xL expression may depend on NF-κB activity [64]. Indicative for its critical role, Bcl-2 overexpression reduced basic apoptosis and sensitivity of melanoma cells for proapoptotic stimuli [65, 66]. Despite the well accepted role of Bcl-2 in melanocyte survival, its contribution to chemoresistance of metastasized melanoma remains unclear, because high Bcl-2 expression in primary melanomas did not correlate with a worsening of prognosis [67], and even reduced expression levels were found in metastases, where Bcl-xL and Mcl-1 were upregulated [68].

Also expression of proapoptotic family members was found in melanoma cells as Bax, Bak, Bid, Bad, PUMA and Noxa [69-71], whereas others as Bcl-xS and Bik/Nbk were lacking [72, 73]. Proapoptotic Bcl-2 proteins may also be upregulated in course of chemotherapy. Thus, taurolidine-induced apoptosis in melanomas correlated with enhanced Bax and reduced Bcl-2 expression [74], and bortezomib induced expression of Noxa [75]. Also a prognostic value of proapoptotic Bcl-2 proteins was found, namely down-regulated Bax and Bak in primary melanomas correlated with unfavorable prognosis [76].

TRANSCRIPTIONAL REGULATION AND SIGNAL CASCADES CONTROLLING Bcl-2 PROTEINS

Constitutive activation of central survival pathways as mitogen-activated protein kinases (MAPKs), protein kinase B (PKB/Akt) and nuclear factor-kappaB (NF-κ B) characteristically occur in cancer cells, and substantial evidence connects them with chemoresistance [77]. The canonical MAPK pathway is activated downstream of receptor tyrosine kinases (RTK) and results in successive phosphorylation of Raf, MEK (MAP/extracellular signal-regulated kinase) and ERK1/2 (extracellular signal-regulated kinases) [78]. On the other hand, Akt is activated by either RTKs or G-protein-coupled receptors [79]. MAPKs and Akt mediate the phosphorylation of multiple apoptosis regulators, and MAPKs in addition lead to the activation of many different transcription factors. Especially, both Akt and ERK may result in activation of the NF-κ B pathway, which triggers the induction of antiapoptotic factors such as IAP proteins and Bcl-xL [80].

Different cell death signals as well as growth factor deprivation are linked with a regulation of several Bcl-2 proteins. Thus, Bax, Noxa, Puma, Bik/Nbk and Bid are upregulated by p53 [81-83]. Bim can be upregulated by FoxO-3A, CEBPα (CCAAT-enhancer binding protein-α) or CHOP (CEBP homologous protein) [84, 85]. In contrast, transcriptional up-regulation of antiapoptotic Bcl-2 proteins often depends on survival signals, as Bcl-xL is up-regulated by the JAK-STAT pathway [86].

Several Bcl-2 proteins are in addition regulated by protein modification. Thus Mcl-1 is characterized by an only short half-life due to its degradation through the proteasome pathway, which can be slowed down by phosphorylation through ERK [87]. In contrast, Bim is inactivated by ERK [88], while Bax and Bad are phosphorylated and inactivated by either ERK or Akt [89, 90]. Hereby, either phosphorylation of Bad, by MAPKs (serine 112) or Akt (serine 136), is sufficient for its inhibition [91]. In contrast, phosphorylation of Bax by Glycogen synthase kinase-3beta (GSK-3β) promotes its activation [92]. Also Bak is activated in response to stress-activated protein kinases as MEKK1 and JNK1, but it seems not to be phosphorylated itself. Intermediate regulators as possibly BH3-only proteins may be employed [93].

Melanoma is characterized by constitutive ERK1/2 expression [94, 95], which may result from activating mutations in B-Raf (60%) and N-Ras (30%) [96, 97]. Thus inactivation of Bad and Bim through MAPK phosphorylation as well as downregulation of PUMA and upregulation of Mcl-1 by MAPKs can be assumed as contributing to melanoma cell survival and chemoresistance [98-100].

The transcription factors activated by MAPKs in melanocytic cells enclose MITF, which particularly accounts for high Bcl-2 expression [101], as well as factors of the Ets or CREB/ATF families, which may be upregulated by MAPKs and induce Bcl-2 and/or Bcl-xL [102-104]. Other pro-survival activities in melanoma cells have been reported for ATF-1, ATF-2 and CREB [105, 106].

Several antiapoptotic activities of PKB/Akt have been identified in melanoma cells, such as Akt-mediated phosphorylation of Bad [107] and activation of the NF-κB pathway through an Akt-mediated pathway [108].

THERAPEUTIC STRATEGIES BASED ON Bcl-2 PROTEINS AND CONCLUSIONS

Because of the critical role of the mitochondrial pathway in melanoma, approaches targeting anti- and proapoptotic Bcl-2 proteins are of particular interest. This may be achieved by targeting survival pathways, due to their control over the Bcl-2 protein expression. Thus, applying MAPK inhibitors induced basic apoptosis and sensitized for pro-apoptotic strategies, which correlated to activation of Bad and of Bax in vitro as well as in mouse models [109-111].

Proteasome inhibitors were applied to induce apoptosis via inhibition of NF-κB. In addition, recent evidence suggested a critical contribution of up-regulation of NOXA which appeared early after proteasome inhibition and correlated with apoptosis [112, 113]. As a contrary effect however, also antiapoptotic Bcl-2 proteins may be upregulated as Mcl-1, which is degraded by the proteasome pathway. Thus, pro- and antiapoptotic Bcl-2 proteins upregulated by proteasome inhibitors appear in balance, and better therapeutic effects may be obtained with suitable combinations, as recently shown for Mcl-1 siRNA [114, 115].

Approaches directly targeting Bcl-2 proteins in melanoma appear of particular interest. Thus, Bcl-2 antisense oligonucleotide strategies were established. Both in vitro and in mouse models, melanoma cells were sensitized for the chemotherapeutic dacarbazine [116]. Also, phase I/II clinical trials showed positive results [117], and a large phase III trial (dacarbazine + Bcl-2 antisense), completed in 2003, showed improvements of the clinical response. Significant improvement of the overall survival was found, however, only in a subgroup of patients with low serum LDH [118].

Complicating an antisense strategy, Bcl-2 expression may also be reduced in metastatic melanoma [119], and other antiapoptotic Bcl-2 proteins such as Mcl-1 or Bcl-xL may substitute for Bcl-2 [120]. Also, antisense strategies have been developed for these proteins, which similarly enhanced chemosensitivity in vitro and in mouse models [121, 122]. Due to high expression of several antiapoptotic Bcl-2 proteins in melanoma, a simultaneous targeting may be necessary [119, 123], which may however be difficult to realize in the clinic. Other approaches used oligonucleotides directed against specific splice sites as the 5'-splice site of Bcl-xL, which resulted in reduced ratio of Bcl-xL to Bcl-xS in breast cancer cells [124].

As pro- and antiapoptotic Bcl-2 proteins are in balance to control the mitochondrial pathway, the overexpression of proapoptotic Bcl-2 proteins appears as an alternative strategy for the targeting of antiapoptotic factors. The efficacy of such strategies has been demonstrated in several in vitro studies, where apoptosis was efficiently induced in melanoma cells and chemosensitivity was increased by the exogeneous overexpression of Bcl-xS, Bik/NBK, Bax, Bcl-xAK or Noxa [125-128].

Related with such strategies, new developments try to mimic the BH3 domain of proapoptotic Bcl-2 proteins, which is supposed to bear the main proapoptotic potential [129]. These BH3 mimetics are peptides or small molecules structurally related to different BH3 domains, and depending on their structure, they reveal distinct specificities for blocking different antiapoptotic Bcl-2 proteins [130].

Gossypol is a naturally occurring BH3 mimetic isolated from cotton seeds, which binds Bcl-xL and Bcl-2. It triggered apoptosis even in Bcl-2- or Bcl-xL-overexpressing cells or such cells that were deficient for both Bax and Bak, which are otherwise resistant to chemotherapy [131, 132]. Also in melanoma cell lines, Gossypol efficiently induced cell death [133]. Another example that induced apoptosis in melanoma, lymphoma and pancreatic carcinoma cells is a Bim-related BH3 domain linked to the HIV TAT protein for better membrane transduction (TAT-Bim) [134].

Much work in different tumors has been done with the small molecule BH3-mimetic ABT-737, which was identified by systematic screening [135]. It inhibits Bcl-2, Bcl-xL and Bcl-w but appears as inactive against Mcl-1 and A1/Bfl-1. Several studies demonstrated a sensitization of tumor cells for chemotherapy [136-139] or, as shown in melanoma cells, it enhanced the proapoptotic effects of co-cultured T-cells [140].

In particular, resistance to MAPK inhibition based on high levels of antiapoptotic Bcl-2 proteins was overcome in melanoma cells by another small molecule BH3 mimetic (TW-37) developed by computer modeling for binding to Mcl-1, Bcl-xL and Bcl-2 [141]. The computer-based design of BH3 mimetics may even allow a further improvement of their efficacy, particularly the simultaneous targeting of all antiapoptotic Bcl-2 proteins is aimed [142].

In summary, dysregulation of Bcl-2 proteins appears of critical importance for melanoma cell survival and drug resistance, and among the fast increasing number of new targeted therapies, those, which affect Bcl-2 proteins, may especially apply for melanoma. These are in particular: i) blocking of survival pathways to control Bcl-2 protein expression, ii) antisense strategies against antiapoptotic Bcl-2 proteins, iii) gene therapy approaches based on overexpression of proapoptotic Bcl-2 proteins and iv) further development of BH3 mimetics. Finally, as a large body of preclinical and clinical evidence demonstrates, highly aggressive tumors as melanoma may not be defeated by monotherapies, rather combinations of several signaling effectors should be envisioned. The challenge of the future will be to identify suitable combinations which will also prove efficient in the clinic, and strategies targeting Bcl-2 proteins will play a dominant role.

Fig. (3). Survival pathways involved in regulation of Bcl-2 proteins.

Fig. (3). Survival pathways involved in regulation of Bcl-2 proteins.

Open in a new tab

Four survival pathways (MAPK, PKB-Akt, IKK, JAK/Stat) are indicated which are linked to a number of transcription factors. Some transcription factors are listed here (NF-κB, Ets1/2, CREB/ATF family, MITF and FoxO, p53, STAT), which control the expression of Bcl-2 proteins.

REFERENCES

  • 1.Jemal A, Siegel R, Ward E, Hao YP, Xu JQ, Murray T, Thun MJ. Cancer statistics, 2008. CA Cancer J. Clin. 2008;58:71–96. doi: 10.3322/CA.2007.0010. [DOI] [PubMed] [Google Scholar]
  • 2.Albreht T, McKee M, Alexe DM, Coleman MP, Martin-Moreno JM. Making progress against cancer in Europe in Europe in 2008. Eur. J. Cancer. 2008 doi: 10.1016/j.ejca.2008.02.015. PMID: 18353629. [DOI] [PubMed] [Google Scholar]
  • 3.Garbe C, Eigentler TK. Diagnosis and treatment of cutaneous melanoma: state of the art 2006. Melanoma Res. 2007;17:117–127. doi: 10.1097/CMR.0b013e328042bb36. [DOI] [PubMed] [Google Scholar]
  • 4.Schadendorf D, Ugurel S, Schuler-Thurner B, Nestle FO, Enk A, Brocker EB, Grabbe S, Rittgen W, Edler L, Sucker A, Zimpfer-Rechner C, Berger T, Kamarashev J, Burg G, Jonuleit H, Tuttenberg A, Becker JC, Keikavoussi P, Kampgen E, Schuler G. Dacarbazine (DTIC) versus vaccination with autologous peptide-pulsed dendritic cells (DC) in first-line treatment of patients with metastatic melanoma: a randomized phase III trial of the DC study group of the DeCOG. Ann. Oncol. 2006;17:563–570. doi: 10.1093/annonc/mdj138. [DOI] [PubMed] [Google Scholar]
  • 5.Keilholz U, Punt CJ, Gore M, Kruit W, Patel P, Lienard D, Thomas J, Proebstle TM, Schmittel A, Schadendorf D, Velu T, Negrier S, Kleeberg U, Lehman F, Suciu S, Eggermont AM. Dacarbazine, cisplatin, and interferon-alfa-2b with or without interleukin-2 in metastatic melanoma: a randomized phase III trial (18951) of the European Organisation for Research and Treatment of Cancer Melanoma Group. J. Clin. Oncol. 2005;23:6747–6755. doi: 10.1200/JCO.2005.03.202. [DOI] [PubMed] [Google Scholar]
  • 6.Fischer U, Schulze-Osthoff K. New approaches and therapeutics targeting apoptosis in disease. Pharmacol. Rev. 2005;57:187–215. doi: 10.1124/pr.57.2.6. [DOI] [PubMed] [Google Scholar]
  • 7.Reed JC, Pellecchia M. Apoptosis-based therapies for hematologic malignancies. Blood. 2005;106:408–418. doi: 10.1182/blood-2004-07-2761. [DOI] [PubMed] [Google Scholar]
  • 8.Kerr JF, Wyllie AH, Currie AR. Apoptosis: a basic biological phenomenon with wide-ranging implications in tissue kinetics. Br. J. Cancer. 1972;26:239–257. doi: 10.1038/bjc.1972.33. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 9.Roos WP, Kaina B. DNA damage-induced cell death by apoptosis. Trends Mol. Med. 2006;12:440–450. doi: 10.1016/j.molmed.2006.07.007. [DOI] [PubMed] [Google Scholar]
  • 10.Clegg HV, Itahana K, Zhang YP. Unlocking the Mdm2-p53 loop - Ubiquitin is the key. Cell Cycle. 2008;7:287–292. doi: 10.4161/cc.7.3.5358. [DOI] [PubMed] [Google Scholar]
  • 11.Roos WP, Kaina B. DNA damage-induced cell death by apoptosis. Trends Mol. Med. 2006;12:440–450. doi: 10.1016/j.molmed.2006.07.007. [DOI] [PubMed] [Google Scholar]
  • 12.Mathai JP, Germain M, Marcellus RC, Shore GC. Induction and endoplasmic reticulum location of BIK/NBK in response to apoptotic signaling by E1A and p53. Oncogene. 2002;21:2534–2544. doi: 10.1038/sj.onc.1205340. [DOI] [PubMed] [Google Scholar]
  • 13.Yu J, Zhang L. The transcriptional targets of p53 in apoptosis control. Biochem. Biophys. Res. Commun. 2005;331:851–858. doi: 10.1016/j.bbrc.2005.03.189. [DOI] [PubMed] [Google Scholar]
  • 14.Schuler M, Green DR. Transcription, apoptosis and p53: catch-22. Trends Genet. 2005;21:182–187. doi: 10.1016/j.tig.2005.01.001. [DOI] [PubMed] [Google Scholar]
  • 15.Youle RJ, Strasser A. The BCL-2 protein family: opposing activities that mediate cell death. Nat. Rev. Mol. Cell Biol. 2008;9:47–59. doi: 10.1038/nrm2308. [DOI] [PubMed] [Google Scholar]
  • 16.Er E, Oliver L, Cartron PF, Juin P, Manon S, Vallette FM. Mitochondria as the target of the pro-apoptotic protein Bax. Biochim. Biophys. Acta Bioenerg. 2006;1757:1301–1311. doi: 10.1016/j.bbabio.2006.05.032. [DOI] [PubMed] [Google Scholar]
  • 17.Saikumar P, Mikhailova M, Pandeswara SL. Regulation of caspase-9 activity by differential binding to the apoptosome complex. Front Biosci. 2007;12:3343–3354. doi: 10.2741/2317. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 18.Los M, Stroh C, Janicke RU, Engels IH, Schulze-Osthoff K. Caspases: more than just killers? Trends Immunol. 2001;22:31–34. doi: 10.1016/s1471-4906(00)01814-7. [DOI] [PubMed] [Google Scholar]
  • 19.Degterev A, Boyce M, Yuan J. A decade of caspases. Oncogene. 2003;22:8543–8567. doi: 10.1038/sj.onc.1207107. [DOI] [PubMed] [Google Scholar]
  • 20.Fischer U, Janicke RU, Schulze-Osthoff K. Many cuts to ruin: a comprehensive update of caspase substrates. Cell Death Differ. 2003;10:76–100. doi: 10.1038/sj.cdd.4401160. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 21.Lu H, Lu HF, Hou Q, Hou QF, Zhao T, Zhao TF, Zhang H, Zhang HF, Zhang Q, Zhang QF, Wu L, Wu LF, Fan Z, Fan Z. Granzyme M directly cleaves inhibitor of caspase-activated DNase (CAD) to unleash CAD leading to DNA fragmentation. J. Immunol. 2006;177:1171–1178. doi: 10.4049/jimmunol.177.2.1171. [DOI] [PubMed] [Google Scholar]
  • 22.Graziani G, Szabo C. Clinical perspectives of PARP inhibitors. Pharmacol. Res. 2005;52:109–118. doi: 10.1016/j.phrs.2005.02.013. [DOI] [PubMed] [Google Scholar]
  • 23.Shiozaki EN, Shi YG. Caspases, IAPs and Smac/DIABLO: mechanisms from structural biology. Trends Biochem. Sci. 2004;29:486–494. doi: 10.1016/j.tibs.2004.07.003. [DOI] [PubMed] [Google Scholar]
  • 24.Walle LV, Lamkanfi M, Vandenabeele P. The mitochondrial serine protease HtrA2/Omi: an overview. Cell Death Differ. 2008;15:453–460. doi: 10.1038/sj.cdd.4402291. [DOI] [PubMed] [Google Scholar]
  • 25.Lorenzo HK, Susin SA. Therapeutic potential of AIF-mediated caspase-independent programmed cell death. Drug Resist. Updat. 2007;10:235–255. doi: 10.1016/j.drup.2007.11.001. [DOI] [PubMed] [Google Scholar]
  • 26.Tsujimoto Y, Yunis J, Onoratoshowe L, Erikson J, Nowell PC, Croce CM. Molecular-Cloning of the Chromosomal Breakpoint of B-Cell Lymphomas and Leukemias with the T(11-14) Chromosome-Translocation. Science. 1984;224:1403–1406. doi: 10.1126/science.6610211. [DOI] [PubMed] [Google Scholar]
  • 27.Green DR, Evan GI. A matter of life and death. Cancer Cell. 2002;1:19–30. doi: 10.1016/s1535-6108(02)00024-7. [DOI] [PubMed] [Google Scholar]
  • 28.Zamzami N, Kroemer G. The mitochondrion in apoptosis: how Pandora's box opens. Nat. Rev. Mol. Cell Biol. 2001;2:67–71. doi: 10.1038/35048073. [DOI] [PubMed] [Google Scholar]
  • 29.Finucane DM, Bossy-Wetzel E, Waterhouse NJ, Cotter TG, Green DR. Bax-induced caspase activation and apoptosis via cytochrome c release from mitochondria is inhibitable by Bcl-xL. J. Biol. Chem. 1999;274:2225–2233. doi: 10.1074/jbc.274.4.2225. [DOI] [PubMed] [Google Scholar]
  • 30.Van LA, Van KS, Lippens S, Declercq W, Vandenabeele P, Janssens S, Vandenheede JR, Garmyn M, Agostinis P. Activation of p38 MAPK is required for Bax translocation to mitochondria, cytochrome c release and apoptosis induced by UVB irradiation in human keratinocytes. FASEB J. 2004;18:1946–1948. doi: 10.1096/fj.04-2285fje. [DOI] [PubMed] [Google Scholar]
  • 31.Zheng Y, Yamaguchi H, Tian C, Lee MW, Tang H, Wang HG, Chen Q. Arsenic trioxide (As(2)O(3)) induces apoptosis through activation of Bax in hematopoietic cells. Oncogene. 2005;24:3339–3347. doi: 10.1038/sj.onc.1208484. [DOI] [PubMed] [Google Scholar]
  • 32.Willis SN, Chen L, Dewson G, Wei A, Naik E, Fletcher JI, Adams JM, Huang DC. Proapoptotic Bak is sequestered by Mcl-1 and Bcl-xL, but not Bcl-2, until displaced by BH3-only proteins. Genes Dev. 2005;19:1294–1305. doi: 10.1101/gad.1304105. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 33.Mathai JP, Germain M, Marcellus RC, Shore GC. Induction and endoplasmic reticulum location of BIK/NBK in response to apoptotic signaling by E1A and p53. Oncogene. 2002;21:2534–2544. doi: 10.1038/sj.onc.1205340. [DOI] [PubMed] [Google Scholar]
  • 34.Collins NL, Reginato MJ, Paulus JK, Sgroi DC, Labaer J, Brugge JS. G1/S cell cycle arrest provides anoikis resistance through Erk-mediated Bim suppression. Mol. Cell Biol. 2005;25:5282–5291. doi: 10.1128/MCB.25.12.5282-5291.2005. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 35.Willis SN, Adams JM. Life in the balance: how BH3-only proteins induce apoptosis. Curr. Opin. Cell Biol. 2005;17:617–625. doi: 10.1016/j.ceb.2005.10.001. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 36.Daniel PT, Schulze-Osthoff K, Belka C, Guner D. Guardians of cell death: the Bcl-2 family proteins. Essays Biochem. 2003;39:73–88. doi: 10.1042/bse0390073. [DOI] [PubMed] [Google Scholar]
  • 37.Chen L, Willis SN, Wei A, Smith BJ, Fletcher JI, Hinds MG, Colman PM, Day CL, Adams JM, Huang DC. Differential targeting of prosurvival Bcl-2 proteins by their BH3-only ligands allows complementary apoptotic function. Mol. Cell. 2005;17:393–403. doi: 10.1016/j.molcel.2004.12.030. [DOI] [PubMed] [Google Scholar]
  • 38.Willis SN, Chen L, Dewson G, Wei A, Naik E, Fletcher JI, Adams JM, Huang DC. Proapoptotic Bak is sequestered by Mcl-1 and Bcl-xL, but not Bcl-2, until displaced by BH3-only proteins. Genes Dev. 2005;19:1294–1305. doi: 10.1101/gad.1304105. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 39.Cheng EH, Wei MC, Weiler S, Flavell RA, Mak TW, Lindsten T, Korsmeyer SJ. BCL-2, BCL-X(L) sequester BH3 domain-only molecules preventing BAX- and BAK-mediated mitochondrial apoptosis. Mol. Cell. 2001;8:705–711. doi: 10.1016/s1097-2765(01)00320-3. [DOI] [PubMed] [Google Scholar]
  • 40.Gomez-Bougie P, Bataille R, Amiot M. The imbalance between Bim and Mcl-1 expression controls the survival of human myeloma cells. Eur. J. Immunol. 2004;34:3156–3164. doi: 10.1002/eji.200424981. [DOI] [PubMed] [Google Scholar]
  • 41.Clohessy JG, Zhuang J, de Boer J, Gil-Gomez G, Brady HJ. Mcl-1 interacts with truncated Bid and inhibits its induction of cytochrome c release and its role in receptor-mediated apoptosis. J. Biol. Chem. 2006;281:5750–5759. doi: 10.1074/jbc.M505688200. [DOI] [PubMed] [Google Scholar]
  • 42.Kuwana T, Bouchier-Hayes L, Chipuk JE, Bonzon C, Sullivan BA, Green DR, Newmeyer DD. BH3 domains of BH3-only proteins differentially regulate Bax-mediated mitochondrial membrane permeabilization both directly and indirectly. Mol. Cell. 2005;17:525–535. doi: 10.1016/j.molcel.2005.02.003. [DOI] [PubMed] [Google Scholar]
  • 43.Nechushtan A, Smith CL, Lamensdorf I, Yoon SH, Youle RJ. Bax and Bak coalesce into novel mitochondria-associated clusters during apoptosis. J. Cell Biol. 2001;153:1265–1276. doi: 10.1083/jcb.153.6.1265. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 44.Hetz C, Bernasconi P, Fisher J, Lee AH, Bassik MC, Antonsson B, Brandt GS, Iwakoshi NN, Schinzel A, Glimcher LH, Korsmeyer SJ. Proapoptotic BAX and BAK modulate the unfolded protein response by a direct interaction with IRE1alpha. Science. 2006;312:572–576. doi: 10.1126/science.1123480. [DOI] [PubMed] [Google Scholar]
  • 45.Ewings KE, Wiggins CM, Cook SJ. Bim and the pro-survival bcl-2 proteins - Opposites attract, ERK repels. Cell Cycle. 2007;6:2236–2240. doi: 10.4161/cc.6.18.4728. [DOI] [PubMed] [Google Scholar]
  • 46.Akgul C, Moulding DA, Edwards SW. Alternative splicing of Bcl-2-related genes: functional consequences and potential therapeutic applications. Cell Mol. Life Sci. 2004;61:2189–2199. doi: 10.1007/s00018-004-4001-7. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 47.Tanaka S, Saito K, Reed JC. Structure-function analysis of the Bcl-2 oncoprotein - Addition of a heterologous transmembrane domain to portions of the Bcl-2-beta protein restores function as a regulator of cell-survival. J. Biol. Chem. 1993;268:10920–10926. [PubMed] [Google Scholar]
  • 48.Ko JK, Lee MJ, Cho SH, Cho JA, Lee BY, Koh JS, Lee SS, Shim YH, Kim CW. Bfl-1S, a novel alternative splice variant of Bfl-1, localizes in the nucleus via its C-terminus and prevents cell death. Oncogene. 2003;22:2457–2465. doi: 10.1038/sj.onc.1206274. [DOI] [PubMed] [Google Scholar]
  • 49.Boise LH, Gonzalez-Garcia M, Postema CE, Ding L, Lindsten T, Turka LA, Mao X, Nunez G, Thompson CB. bcl-x, a bcl-2-related gene that functions as a dominant regulator of apoptotic cell death. Cell. 1993;74:597–608. doi: 10.1016/0092-8674(93)90508-n. [DOI] [PubMed] [Google Scholar]
  • 50.Shiraiwa N, Inohara N, Okada S, Yuzaki M, Shoji S, Ohta S. An additional form of rat Bcl-x, Bcl-xbeta, generated by an unspliced RNA, promotes apoptosis in promyeloid cells. J. Biol. Chem. 1996;271:13258–13265. doi: 10.1074/jbc.271.22.13258. [DOI] [PubMed] [Google Scholar]
  • 51.Schmitt E, Paquet C, Beauchemin M, Bertrand R. Bcl-xES, a BH4- and BH2-containing antiapoptotic protein, delays Bax oligomer formation and binds Apaf-1, blocking procaspase-9 activation. Oncogene. 2004;23:3915–3931. doi: 10.1038/sj.onc.1207554. [DOI] [PubMed] [Google Scholar]
  • 52.Hossini AM, Geilen CC, Fecker LF, Daniel PT, Eberle J. A novel Bcl-x splice product, Bcl-xAK, triggers apoptosis in human melanoma cells without BH3 domain. Oncogene. 2006;25:2160–2169. doi: 10.1038/sj.onc.1209253. [DOI] [PubMed] [Google Scholar]
  • 53.Viegas LR, Vicent GP, Baranao JL, Beato M, Pecci A. Steroid hormones induce bcl-X gene expression through direct activation of distal promoter P4. J. Biol. Chem. 2004;279:9831–9839. doi: 10.1074/jbc.M312402200. [DOI] [PubMed] [Google Scholar]
  • 54.Li CY, Chu JY, Yu JK, Huang XQ, Liu XJ, Shi L, Che YC, Xie JY. Regulation of alternative splicing of Bcl-x by IL-6, GM-CSF and TPA. Cell Res. 2004;14:473–479. doi: 10.1038/sj.cr.7290250. [DOI] [PubMed] [Google Scholar]
  • 55.Paronetto MP, Achsel T, Massiello A, Chalfant CE, Sette C. The RNA-binding protein Sam68 modulates the alternative splicing of Bcl-x. J. Cell Biol. 2007;176:929–939. doi: 10.1083/jcb.200701005. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 56.Raisova M, Bektas M, Wieder T, Daniel P, Eberle J, Orfanos CE, Geilen CC. Resistance to CD95/Fas-induced and ceramide-mediated apoptosis of human melanoma cells is caused by a defective mitochondrial cytochrome c release. FEBS Lett. 2000;473:27–32. doi: 10.1016/s0014-5793(00)01491-5. [DOI] [PubMed] [Google Scholar]
  • 57.Thomas WD, Zhang XD, Franco AV, Nguyen T, Hersey P. TNF-related apoptosis-inducing ligand-induced apoptosis of melanoma is associated with changes in mitochondrial membrane potential and perinuclear clustering of mitochondria. J. Immunol. 2000;165:5612–5620. doi: 10.4049/jimmunol.165.10.5612. [DOI] [PubMed] [Google Scholar]
  • 58.Eberle J, Kurbanov BM, Hossini AM, Trefter U, Fecker LF. Overcoming apoptosis deficiency of melanoma - Hope for new therapeutic approaches. Drug Resist. Updat. 2007;10:218–234. doi: 10.1016/j.drup.2007.09.001. [DOI] [PubMed] [Google Scholar]
  • 59.Selzer E, Schlagbauer-Wadl H, Okamoto I, Pehamberger H, Potter R, Jansen B. Expression of Bcl-2 family members in human melanocytes, in melanoma metastases and in melanoma cell lines. Melanoma Res. 1998;8:197–203. doi: 10.1097/00008390-199806000-00001. [DOI] [PubMed] [Google Scholar]
  • 60.Hossini AM, Eberle J, Fecker LF, Orfanos CE, Geilen CC. Conditional expression of exogenous Bcl-X(S) triggers apoptosis in human melanoma cells in vitro and delays growth of melanoma xenografts. FEBS Lett. 2003;553:250–256. doi: 10.1016/s0014-5793(03)01017-2. [DOI] [PubMed] [Google Scholar]
  • 61.Wolter KG, Verhaegen M, Fernandez Y, Nikolovska-Coleska Z, Riblett M, Martin de la Vega C, Wang S, Soengas MS. Therapeutic window for melanoma treatment provided by selective effects of the proteasome on Bcl-2 proteins. Cell Death Differ. 2007;14:1605–1616. doi: 10.1038/sj.cdd.4402163. [DOI] [PubMed] [Google Scholar]
  • 62.Raisova M, Hossini AM, Eberle J, Riebeling C, Wieder T, Sturm I, Daniel PT, Orfanos CE, Geilen CC. The Bax/Bcl-2 ratio determines the susceptibility of human melanoma cells to CD95/Fas-mediated apoptosis. J. Invest. Dermatol. 2001;117:333–340. doi: 10.1046/j.0022-202x.2001.01409.x. [DOI] [PubMed] [Google Scholar]
  • 63.McGill GG, Horstmann M, Widlund HR, Du J, Motyckova G, Nishimura EK, Lin YL, Ramaswamy S, Avery W, Ding HF, Jordan SA, Jackson IJ, Korsmeyer SJ, Golub TR, Fisher DE. Bcl2 regulation by the melanocyte master regulator Mitf modulates lineage survival and melanoma cell viability. Cell. 2002;109:707–718. doi: 10.1016/s0092-8674(02)00762-6. [DOI] [PubMed] [Google Scholar]
  • 64.Ravi R, Bedi A. NF-kappaB in cancer--a friend turned foe. Drug Resist. Updat. 2004;7:53–67. doi: 10.1016/j.drup.2004.01.003. [DOI] [PubMed] [Google Scholar]
  • 65.Raisova M, Goltz G, Bektas M, Bielawska A, Riebeling C, Hossini AM, Eberle J, Hannun YA, Orfanos CE, Geilen CC. Bcl-2 overexpression prevents apoptosis induced by ceramidase inhibitors in malignant melanoma and HaCaT keratinocytes. FEBS Lett. 2002;516:47–52. doi: 10.1016/s0014-5793(02)02472-9. [DOI] [PubMed] [Google Scholar]
  • 66.Kurbanov BM, Geilen CC, Fecker LF, Orfanos CE, Eberle J. Efficient TRAIL-R1/DR4-mediated apoptosis in melanoma cells by tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) J. Invest. Dermatol. 2005;125:1010–1019. doi: 10.1111/j.0022-202X.2005.23900.x. [DOI] [PubMed] [Google Scholar]
  • 67.Fecker LF, Geilen CC, Tchernev G, Trefzer U, Assaf C, Kurbanov BM, Schwarz C, Daniel PT, Eberle J. Loss of proapoptotic Bcl-2-related multidomain proteins in primary melanomas is associated with poor prognosis. J. Invest. Dermatol. 2006;126:1366–1371. doi: 10.1038/sj.jid.5700192. [DOI] [PubMed] [Google Scholar]
  • 68.Zhuang L, Lee CS, Scolyer RA, McCarthy SW, Zhang XD, Thompson JF, Hersey P. Mcl-1, Bcl-XL and Stat3 expression are associated with progression of melanoma whereas Bcl-2, AP-2 and MITF levels decrease during progression of melanoma. Mod. Pathol. 2007;20:416–426. doi: 10.1038/modpathol.3800750. [DOI] [PubMed] [Google Scholar]
  • 69.Karst AM, Dai DL, Martinka M, Li G. PUMA expression is significantly reduced in human cutaneous melanomas. Oncogene. 2005;24:1111–1116. doi: 10.1038/sj.onc.1208374. [DOI] [PubMed] [Google Scholar]
  • 70.Armstrong JL, Veal GJ, Redfern CPF, Lovat PE. Role of Noxa in p53-independent fenretinide-induced apoptosis of neuroectodermal tumours. Apoptosis. 2007;12:613–622. doi: 10.1007/s10495-006-0020-1. [DOI] [PubMed] [Google Scholar]
  • 71.Eberle J, Kurbanov BM, Hossini AM, Trefter U, Fecker LF. Overcoming apoptosis deficiency of melanoma - Hope for new therapeutic approaches. Drug Resist. Updat. 2007;10:218–234. doi: 10.1016/j.drup.2007.09.001. [DOI] [PubMed] [Google Scholar]
  • 72.Hossini AM, Eberle J, Fecker LF, Orfanos CE, Geilen CC. Conditional expression of exogenous Bcl-X(S) triggers apoptosis in human melanoma cells in vitro and delays growth of melanoma xenografts. FEBS Lett. 2003;553:250–256. doi: 10.1016/s0014-5793(03)01017-2. [DOI] [PubMed] [Google Scholar]
  • 73.Oppermann M, Geilen CC, Fecker LF, Gillissen B, Daniel PT, Eberle J. Caspase-independent induction of apoptosis in human melanoma cells by the proapoptotic Bcl-2-related protein Nbk / Bik. Oncogene. 2005;24:7369–7380. doi: 10.1038/sj.onc.1208890. [DOI] [PubMed] [Google Scholar]
  • 74.Sun BS, Wang JH, Liu LL, Gong SL, Redmond HP. Taurolidine induces apoptosis of murine melanoma cells in vitro and in vivo by modulation of the Bcl-2 family proteins. J. Surg. Oncol. 2007 doi: 10.1002/jso.20827. [DOI] [PubMed] [Google Scholar]
  • 75.Qin JZ, Xin H, Sitailo LA, Denning MF, Nickoloff BJ. Enhanced Killing of Melanoma Cells by Simultaneously Targeting Mcl-1 and NOXA. Cancer Res. 2006;66:9636–9645. doi: 10.1158/0008-5472.CAN-06-0747. [DOI] [PubMed] [Google Scholar]
  • 76.Fecker LF, Geilen CC, Tchernev G, Trefzer U, Assaf C, Kurbanov BM, Schwarz C, Daniel PT, Eberle J. Loss of proapoptotic Bcl-2-related multidomain proteins in primary melanomas is associated with poor prognosis. J. Invest. Dermatol. 2006;126:1366–1371. doi: 10.1038/sj.jid.5700192. [DOI] [PubMed] [Google Scholar]
  • 77.Smalley KS, Eisen TG. Farnesyl transferase inhibitor SCH66336 is cytostatic, pro-apoptotic and enhances chemosensitivity to cisplatin in melanoma cells. Int. J. Cancer. 2003;105:165–175. doi: 10.1002/ijc.11064. [DOI] [PubMed] [Google Scholar]
  • 78.Dhillon AS, Hagan S, Rath O, Kolch W. MAP kinase signalling pathways in cancer. Oncogene. 2007;26:3279–3290. doi: 10.1038/sj.onc.1210421. [DOI] [PubMed] [Google Scholar]
  • 79.Manning BD, Cantley LC. AKT/PKB signaling: navigating downstream. Cell. 2007;129:1261–1274. doi: 10.1016/j.cell.2007.06.009. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 80.Dolcet X, Llobet D, Pallares J, Matias-Guiu X. NF-kB in development and progression of human cancer. Virchows Arch. 2005;446:475–482. doi: 10.1007/s00428-005-1264-9. [DOI] [PubMed] [Google Scholar]
  • 81.Mathai JP, Germain M, Marcellus RC, Shore GC. Induction and endoplasmic reticulum location of BIK/NBK in response to apoptotic signaling by E1A and p53. Oncogene. 2002;21:2534–2544. doi: 10.1038/sj.onc.1205340. [DOI] [PubMed] [Google Scholar]
  • 82.Yu J, Zhang L. The transcriptional targets of p53 in apoptosis control. Biochem. Biophys. Res. Commun. 2005;331:851–858. doi: 10.1016/j.bbrc.2005.03.189. [DOI] [PubMed] [Google Scholar]
  • 83.Schuler M, Green DR. Transcription, apoptosis and p53: catch-22. Trends Genet. 2005;21:182–187. doi: 10.1016/j.tig.2005.01.001. [DOI] [PubMed] [Google Scholar]
  • 84.Barreyro FJ, Kobayashi S, Bronk SF, Werneburg NW, Malhi H, Gores GJ. Transcriptional regulation of Bim by FoxO3A mediates hepatocyte lipoapoptosis. J. Biol. Chem. 2007;282:27141–27154. doi: 10.1074/jbc.M704391200. [DOI] [PubMed] [Google Scholar]
  • 85.Puthalakath H, O'Reilly LA, Gunn P, Lee L, Kelly PN, Huntington ND, Hughes PD, Michalak EM, McKimm-Breschkin J, Motoyama N, Gotoh T, Akira S, Bouillet P, Strasser A. ER stress triggers apoptosis by activating BH3-only protein Bim. Cell. 2007;129:1337–1349. doi: 10.1016/j.cell.2007.04.027. [DOI] [PubMed] [Google Scholar]
  • 86.Dumon S, Santos SCR, Debierre-Grockiego F, Gouilleux-Gruart V, Cocault L, Boucheron C, Mollat P, Gisselbrecht S, Gouilleux F. IL-3 dependent regulation of Bcl-x(L) gene expression by STAT5 in a bone marrow derived cell line. Oncogene. 1999;18:4191–4199. doi: 10.1038/sj.onc.1202796. [DOI] [PubMed] [Google Scholar]
  • 87.Domina AM, Vrana JA, Gregory MA, Hann SR, Craig RW. MCL1 is phosphorylated in the PEST region and stabilized upon ERK activation in viable cells, and at additional sites with cytotoxic okadaic acid or taxol. Oncogene. 2004;23:5301–5315. doi: 10.1038/sj.onc.1207692. [DOI] [PubMed] [Google Scholar]
  • 88.Ley R, Balmanno K, Hadfield K, Weston C, Cook SJ. Activation of the ERK1/2 signaling pathway promotes phosphorylation and proteasome-dependent degradation of the BH3-only protein, Bim. J. Biol. Chem. 2003;278:18811–18816. doi: 10.1074/jbc.M301010200. [DOI] [PubMed] [Google Scholar]
  • 89.Parikh N, Sade H, Kurian L, Sarin A. The bax n terminus is required for negative regulation by the mitogen-activated protein kinase kinase and Akt signaling pathways in T cells. J. Immunol. 2004;173:6220–6227. doi: 10.4049/jimmunol.173.10.6220. [DOI] [PubMed] [Google Scholar]
  • 90.Antignani A, Youle RJ. A chimeric protein induces tumor cell apoptosis by delivering the human Bcl-2 family BH3-only protein bad. Biochemistry. 2005;44:4074–4082. doi: 10.1021/bi0477687. [DOI] [PubMed] [Google Scholar]
  • 91.She QB, Solit DB, Ye Q, O'Reilly KE, Lobo J, Rosen N. The BAD protein integrates survival signaling by EGFR/MAPK and PI3K/Akt kinase pathways in PTEN-deficient tumor cells. Cancer Cell. 2005;8:287–297. doi: 10.1016/j.ccr.2005.09.006. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 92.Linseman DA, Butts BD, Precht TA, Phelps RA, Le SS, Laessig TA, Bouchard RJ, Florez-McClure ML, Heidenreich KA. Glycogen synthase kinase-3 beta phosphorylates bax and promotes its mitochondrial localization during neuronal apoptosis. J. Neurosci. 2004;24:9993–10002. doi: 10.1523/JNEUROSCI.2057-04.2004. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 93.Ihrlund LS, Hernlund E, Viktorsson K, Panaretakis T, Barna G, Sabapathy K, Linder S, Shoshan MC. Two distinct steps of Bak regulation during apoptotic stress signaling: different roles of MEKK1 and JNK1. Exp. Cell Res. 2006;312:1581–1589. doi: 10.1016/j.yexcr.2006.01.023. [DOI] [PubMed] [Google Scholar]
  • 94.Cohen C, Zavala-Pompa A, Sequeira JH, Shoji M, Sexton DG, Cotsonis G, Cerimele F, Govindarajan B, Macaron N, Arbiser JL. Mitogen-actived protein kinase activation is an early event in melanoma progression. Clin. Cancer Res. 2002;8:3728–3733. [PubMed] [Google Scholar]
  • 95.Mirmohammadsadegh A, Mota R, Gustrau A, Hassan M, Nambiar S, Marini A, Bojar H, Tannapfel A, Hengge UR. ERK1/2 Is Highly Phosphorylated in Melanoma Metastases and Protects Melanoma Cells from Cisplatin-Mediated Apoptosis. J. Invest. Dermatol. 2007;127:2207–2215. doi: 10.1038/sj.jid.5700870. [DOI] [PubMed] [Google Scholar]
  • 96.Davies H, Bignell GR, Cox C, Stephens P, Edkins S, Clegg S, Teague J, Woffendin H, Garnett MJ, Bottomley W, Davis N, Dicks E, Ewing R, Floyd Y, Gray K, Hall S, Hawes R, Hughes J, Kosmidou V, Menzies A, Mould C, Parker A, Stevens C, Watt S, Hooper S, Wilson R, Jayatilake H, Gusterson BA, Cooper C, Shipley J, Hargrave D, Pritchard-Jones K, Maitland N, Chenevix-Trench G, Riggins GJ, Bigner DD, Palmieri G, Cossu A, Flanagan A, Nicholson A, Ho JW, Leung SY, Yuen ST, Weber BL, Seigler HF, Darrow TL, Paterson H, Marais R, Marshall CJ, Wooster R, Stratton MR, Futreal PA. Mutations of the BRAF gene in human cancer. Nature. 2002;417:949–954. doi: 10.1038/nature00766. [DOI] [PubMed] [Google Scholar]
  • 97.Edlundh-Rose E, Egyhazi S, Omholt K, Mansson-Brahme E, Platz A, Hansson J, Lundeberg J. NRAS and BRAF mutations in melanoma tumours in relation to clinical characteristics: a study based on mutation screening by pyrosequencing. Melanoma Res. 2006;16:471–478. doi: 10.1097/01.cmr.0000232300.22032.86. [DOI] [PubMed] [Google Scholar]
  • 98.Eisenmann KM, VanBrocklin MW, Staffend NA, Kitchen SM, Koo HM. Mitogen-activated protein kinase pathway-dependent tumor-specific survival signaling in melanoma cells through inactivation of the proapoptotic protein bad. Cancer Res. 2003;63:8330–8337. [PubMed] [Google Scholar]
  • 99.Panka DJ, Atkins MB, Mier JW. Targeting the mitogen-activated protein kinase pathway in the treatment of malignant melanoma. Clin. Cancer Res. 2006;12:2371s–2375s. doi: 10.1158/1078-0432.CCR-05-2539. [DOI] [PubMed] [Google Scholar]
  • 100.Wang YF, Jiang CF, Kiejda KF, Gillespie SF, Zhang XF, Hersey P. Apoptosis Induction in Human Melanoma Cells by Inhibition of MEK Is Caspase-Independent and Mediated by the Bcl-2 Family Members PUMA, Bim, and Mcl-1. Clin. Cancer Res. 2007;13:4934–4942. doi: 10.1158/1078-0432.CCR-07-0665. [DOI] [PubMed] [Google Scholar]
  • 101.McGill GG, Horstmann M, Widlund HR, Du J, Motyckova G, Nishimura EK, Lin YL, Ramaswamy S, Avery W, Ding HF, Jordan SA, Jackson IJ, Korsmeyer SJ, Golub TR, Fisher DE. Bcl2 regulation by the melanocyte master regulator Mitf modulates lineage survival and melanoma cell viability. Cell. 2002;109:707–718. doi: 10.1016/s0092-8674(02)00762-6. [DOI] [PubMed] [Google Scholar]
  • 102.Sevilla L, Aperlo C, Dulic V, Chambard JC, Boutonnet C, Pasquier O, Pognonec P, Boulukos KE. The Ets2 transcription factor inhibits apoptosis induced by colony-stimulating factor 1 deprivation of macrophages through a Bcl-x(L)-dependent mechanism. Mol. Cell. Biol. 1999;19:2624–2634. doi: 10.1128/mcb.19.4.2624. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 103.Yu Z, Shah DM. Curcumin down-regulates Ets-1 and Bcl-2 expression in human endometrial carcinoma HEC-1-A cells. Gynecol. Oncol. 2007 doi: 10.1016/j.ygyno.2007.05.024. PMID: 17590421. [DOI] [PubMed] [Google Scholar]
  • 104.Xiang H, Wang JH, Boxer LM. Role of the cyclic AMP response element in the bcl-2 promoter in the regulation of endogenous Bcl-2 expression and apoptosis in murine B cells. Mol. Cell. Biol. 2006;26:8599–8606. doi: 10.1128/MCB.01062-06. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 105.Nyormoi O, Bar-Eli M. Transcriptional regulation of metastasis-related genes in human melanoma. Clin. Exp. Metastasis. 2003;20:251–263. doi: 10.1023/a:1022991302172. [DOI] [PubMed] [Google Scholar]
  • 106.Bhoumik A, Jones N, Ronai Z. Transcriptional switch by activating transcription factor 2-derived peptide sensitizes melanoma cells to apoptosis and inhibits their tumorigenicity. Proc. Natl. Acad. Sci. USA. 2004;101:4222–4227. doi: 10.1073/pnas.0400195101. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 107.Li G, Kalabis J, Xu XW, Meier F, Oka M, Bogenrieder T, Herlyn M. Reciprocal regulation of MelCAM and AKT in human melanoma. Oncogene. 2003;22:6891–6899. doi: 10.1038/sj.onc.1206819. [DOI] [PubMed] [Google Scholar]
  • 108.Dhawan P, Singh AB, Ellis DL, Richmond A. Constitutive activation of Akt/protein kinase B in melanoma leads to up-regulation of nuclear factor-kappaB and tumor progression. Cancer Res. 2002;62:7335–7342. [PubMed] [Google Scholar]
  • 109.Eisenmann KM, VanBrocklin MW, Staffend NA, Kitchen SM, Koo HM. Mitogen-activated protein kinase pathway-dependent tumor-specific survival signaling in melanoma cells through inactivation of the proapoptotic protein bad. Cancer Res. 2003;63:8330–8337. [PubMed] [Google Scholar]
  • 110.Zhang XD, Borrow JM, Zhang XY, Nguyen T, Hersey P. Activation of ERK1/2 protects melanoma cells from TRAIL-induced apoptosis by inhibiting Smac/DIABLO release from mitochondria. Oncogene. 2003;22:2869–2881. doi: 10.1038/sj.onc.1206427. [DOI] [PubMed] [Google Scholar]
  • 111.Sharma A, Tran MA, Liang S, Sharma AK, Amin S, Smith CD, Dong C, Robertson GP. Targeting Mitogen-Activated Protein Kinase/Extracellular Signal-Regulated Kinase Kinase in the Mutant (V600E) B-Raf Signaling Cascade Effectively Inhibits Melanoma Lung Metastases. Cancer Res. 2006;66:8200–8209. doi: 10.1158/0008-5472.CAN-06-0809. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 112.Qin JZ, Ziffra J, Stennett L, Bodner B, Bonish BK, Chaturvedi V, Bennett F, Pollock PM, Trent JM, Hendrix MJC, Rizzo P, Miele L, Nickoloff BJ. Proteasome inhibitors trigger NOXA-mediated apoptosis in melanoma and myeloma cells. Cancer Res. 2005;65:6282–6293. doi: 10.1158/0008-5472.CAN-05-0676. [DOI] [PubMed] [Google Scholar]
  • 113.Fernandez Y, Verhaegen M, Miller TP, Rush JL, Steiner P, Opipari AW Jr, Lowe SW, Soengas MS. Differential regulation of noxa in normal melanocytes and melanoma cells by proteasome inhibition: therapeutic implications. Cancer Res. 2005;65:6294–6304. doi: 10.1158/0008-5472.CAN-05-0686. [DOI] [PubMed] [Google Scholar]
  • 114.Qin JZ, Xin H, Sitailo LA, Denning MF, Nickoloff BJ. Enhanced Killing of Melanoma Cells by Simultaneously Targeting Mcl-1 and NOXA. Cancer Res. 2006;66:9636–9645. doi: 10.1158/0008-5472.CAN-06-0747. [DOI] [PubMed] [Google Scholar]
  • 115.Wolter KG, Verhaegen M, Fernandez Y, Nikolovska-Coleska Z, Riblett M, Martin de la Vega C, Wang S, Soengas MS. Therapeutic window for melanoma treatment provided by selective effects of the proteasome on Bcl-2 proteins. Cell Death Differ. 2007;14:1605–1616. doi: 10.1038/sj.cdd.4402163. [DOI] [PubMed] [Google Scholar]
  • 116.Jansen B, Schlagbauer-Wadl H, Brown BD, Bryan RN, van EA, Muller M, Wolff K, Eichler HG, Pehamberger H. bcl-2 antisense therapy chemosensitizes human melanoma in SCID mice. Nat. Med. 1998;4:232–234. doi: 10.1038/nm0298-232. [DOI] [PubMed] [Google Scholar]
  • 117.Jansen B, Wacheck V, Heere-Ress E, Schlagbauer-Wadl H, Hoeller C, Lucas T, Hoermann M, Hollenstein U, Wolff K, Pehamberger H. Chemosensitisation of malignant melanoma by BCL2 antisense therapy. Lancet. 2000;356:1728–1733. doi: 10.1016/S0140-6736(00)03207-4. [DOI] [PubMed] [Google Scholar]
  • 118.Bedikian AY, Millward M, Pehamberger H, Conry R, Gore M, Trefzer U, Pavlick AC, DeConti R, Hersh EM, Hersey P, Kirkwood JM, Haluska FG. Bcl-2 antisense (oblimersen sodium) plus dacarbazine in patients with advanced melanoma: the Oblimersen Melanoma Study Group. J. Clin. Oncol. 2006;24:4738–4745. doi: 10.1200/JCO.2006.06.0483. [DOI] [PubMed] [Google Scholar]
  • 119.Bush JA, Li G. The role of Bcl-2 family members in the progression of cutaneous melanoma. Clin. Exp. Metastasis. 2003;20:531–539. doi: 10.1023/a:1025874502181. [DOI] [PubMed] [Google Scholar]
  • 120.Zhuang L, Lee CS, Scolyer RA, McCarthy SW, Zhang XD, Thompson JF, Hersey P. Mcl-1, Bcl-XL and Stat3 expression are associated with progression of melanoma whereas Bcl-2, AP-2 and MITF levels decrease during progression of melanoma. Mod. Pathol. 2007;20:416–426. doi: 10.1038/modpathol.3800750. [DOI] [PubMed] [Google Scholar]
  • 121.Thallinger C, Wolschek MF, Wacheck V, Maierhofer H, Gunsberg P, Polterauer P, Pehamberger H, Monia BP, Selzer E, Wolff K, Jansen B. Mcl-1 antisense therapy chemosensitizes human melanoma in a SCID mouse xenotransplantation model. J. Invest Dermatol. 2003;120:1081–1086. doi: 10.1046/j.1523-1747.2003.12252.x. [DOI] [PubMed] [Google Scholar]
  • 122.Heere-Ress E, Thallinger C, Lucas T, Schlagbauer-Wadl H, Wacheck V, Monia BP, Wolff K, Pehamberger H, Jansen B. Bcl-X(L) is a chemoresistance factor in human melanoma cells that can be inhibited by antisense therapy. Int. J. Cancer. 2002;99:29–34. doi: 10.1002/ijc.10248. [DOI] [PubMed] [Google Scholar]
  • 123.Gautschi O, Tschopp S, Olie RA, Leech SH, Simoes-Wust AP, Ziegler A, Baumann B, Odermatt B, Hall J, Stahel RA, Zangemeister-Wittke U. Activity of a novel bcl-2/bcl-xL-bispecific antisense oligonucleotide against tumors of diverse histologic origins. J. Natl. Cancer Inst. 2001;93:463–471. doi: 10.1093/jnci/93.6.463. [DOI] [PubMed] [Google Scholar]
  • 124.Mercatante DR, Bortner CD, Cidlowski JA, Kole R. Modification of alternative splicing of Bcl-x Pre-mRNA in prostate and breast cancer cells - Analysis of apoptosis and cell death. J. Biol. Chem. 2001;276:16411–16417. doi: 10.1074/jbc.M009256200. [DOI] [PubMed] [Google Scholar]
  • 125.Hossini AM, Eberle J, Fecker LF, Orfanos CE, Geilen CC. Conditional expression of exogenous Bcl-X(S) triggers apoptosis in human melanoma cells in vitro and delays growth of melanoma xenografts. FEBS Lett. 2003;553:250–256. doi: 10.1016/s0014-5793(03)01017-2. [DOI] [PubMed] [Google Scholar]
  • 126.Oppermann M, Geilen CC, Fecker LF, Gillissen B, Daniel PT, Eberle J. Caspase-independent induction of apoptosis in human melanoma cells by the proapoptotic Bcl-2-related protein Nbk / Bik. Oncogene. 2005;24:7369–7380. doi: 10.1038/sj.onc.1208890. [DOI] [PubMed] [Google Scholar]
  • 127.Hossini AM, Geilen CC, Fecker LF, Daniel PT, Eberle J. A novel Bcl-x splice product, Bcl-xAK, triggers apoptosis in human melanoma cells without BH3 domain. Oncogene. 2006;25:2160–2169. doi: 10.1038/sj.onc.1209253. [DOI] [PubMed] [Google Scholar]
  • 128.Hassan M, Alaoui A, Feyen O, Mirmohammadsadegh A, Marini A, Essmann F, Tannapfel A, Gulbins E, Schulze-Osthoff K, Hengge UR. The BH3-only member Noxa causes apoptosis in melanoma cells by multiple pathways. J. Invest. Dermatol. 2007;127:S50. doi: 10.1038/onc.2008.90. [DOI] [PubMed] [Google Scholar]
  • 129.Adams JM, Cory S. The Bcl-2 apoptotic switch in cancer development and therapy. Oncogene. 2007;26:1324–1337. doi: 10.1038/sj.onc.1210220. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 130.Walensky LD, Kung AL, Escher I, Malia TJ, Barbuto S, Wright RD, Wagner G, Verdine GL, Korsmeyer SJ. Activation of apoptosis in vivo by a hydrocarbon-stapled BH3 helix. Science. 2004;305:1466–1470. doi: 10.1126/science.1099191. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 131.Oliver CL, Miranda MB, Shangary S, Land S, Wang S, Johnson DE. (-)-Gossypol acts directly on the mitochondria to overcome Bcl-2- and Bcl-X(L)-mediated apoptosis resistance. Mol. Cancer Ther. 2005;4:23–31. [PubMed] [Google Scholar]
  • 132.Lei X, Chen Y, Du G, Yu W, Wang X, Qu H, Xia B, He H, Mao J, Zong W, Liao X, Mehrpour M, Hao X, Chen Q. Gossypol induces Bax/Bak-independent activation of apoptosis and cytochrome c release via a conformational change in Bcl-2. FASEB J. 2006;20:2147–2149. doi: 10.1096/fj.05-5665fje. [DOI] [PubMed] [Google Scholar]
  • 133.Shelley MD, Hartley L, Fish RG, Groundwater P, Morgan JJG, Mort D, Mason M, Evans A. Stereo-specific cytotoxic effects of gossypol enantiomers and gossypolone in tumour cell lines. Cancer Lett. 1999;135:171–180. doi: 10.1016/s0304-3835(98)00302-4. [DOI] [PubMed] [Google Scholar]
  • 134.Kashiwagi H, McDunn JE, Goedegebuure PS, Gaffney MC, Chang K, Trinkaus K, Piwnica-Worms D, Hotchkiss RS, Hawkins WG. TAT-Bim Induces Extensive Apoptosis in Cancer Cells. Ann. Surg. Oncol. 2007;14:1763–1771. doi: 10.1245/s10434-006-9298-z. [DOI] [PubMed] [Google Scholar]
  • 135.Karl E, Warner K, Zeitlin B, Kaneko T, Wurtzel L, Jin T, Chang J, Wang S, Wang CY, Strieter RM, Nunez G, Polverini PJ, Nor JE. Bcl-2 acts in a proangiogenic signaling pathway through nuclear factor-kappaB and CXC chemokines. Cancer Res. 2005;65:5063–5069. doi: 10.1158/0008-5472.CAN-05-0140. [DOI] [PubMed] [Google Scholar]
  • 136.Oltersdorf T, Elmore SW, Shoemaker AR, Armstrong RC, Augeri DJ, Belli BA, Bruncko M, Deckwerth TL, Dinges J, Hajduk PJ, Joseph MK, Kitada S, Korsmeyer SJ, Kunzer AR, Letai A, Li C, Mitten MJ, Nettesheim DG, Ng S, Nimmer PM, O'Connor JM, Oleksijew A, Petros AM, Reed JC, Shen W, Tahir SK, Thompson CB, Tomaselli KJ, Wang B, Wendt MD, Zhang H, Fesik SW, Rosenberg SH. An inhibitor of Bcl-2 family proteins induces regression of solid tumours. Nature. 2005;435:677–681. doi: 10.1038/nature03579. [DOI] [PubMed] [Google Scholar]
  • 137.Konopleva M, Contractor R, Tsao T, Samudio I, Ruvolo PP, Kitada S, Deng X, Zhai D, Shi YX, Sneed T, Verhaegen M, Soengas M, Ruvolo VR, McQueen T, Schober WD, Watt JC, Jiffar T, Ling X, Marini FC, Harris D, Dietrich M, Estrov Z, McCubrey J, May WS, Reed JC, Andreeff M. Mechanisms of apoptosis sensitivity and resistance to the BH3 mimetic ABT-737 in acute myeloid leukemia. Cancer Cell. 2006;10:375–388. doi: 10.1016/j.ccr.2006.10.006. [DOI] [PubMed] [Google Scholar]
  • 138.van Delft MF, Wei AH, Mason KD, Vandenberg CJ, Chen L, Czabotar PE, Willis SN, Scott CL, Day CL, Cory S, Adams JM, Roberts AW, Huang DC. The BH3 mimetic ABT-737 targets selective Bcl-2 proteins and efficiently induces apoptosis via Bak/Bax if Mcl-1 is neutralized. Cancer Cell. 2006;10:389–399. doi: 10.1016/j.ccr.2006.08.027. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 139.Chauhan D, Velankar M, Brahmandam M, Hideshima T, Podar K, Richardson P, Schlossman R, Ghobrial I, Raje N, Munshi N, Anderson KC. A novel Bcl-2/Bcl-X(L)/Bcl-w inhibitor ABT-737 as therapy in multiple myeloma. Oncogene. 2007;26:2374–2380. doi: 10.1038/sj.onc.1210028. [DOI] [PubMed] [Google Scholar]
  • 140.Lickliter JD, Cox J, McCarron J, Martinez NR, Schmidt CW, Lin H, Nieda M, Nicol AJ. Small-molecule Bcl-2 inhibitors sensitise tumour cells to immune-mediated destruction. Br. J. Cancer. 2007;96:600–608. doi: 10.1038/sj.bjc.6603599. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 141.Verhaegen M, Bauer JA, Martin dl V, Wang G, Wolter KG, Brenner JC, Nikolovska-Coleska Z, Bengtson A, Nair R, Elder JT, Van BM, Carey TE, Bradford CR, Wang S, Soengas MS. A novel BH3 mimetic reveals a mitogen-activated protein kinase-dependent mechanism of melanoma cell death controlled by p53 and reactive oxygen species. Cancer Res. 2006;66:11348–11359. doi: 10.1158/0008-5472.CAN-06-1748. [DOI] [PubMed] [Google Scholar]
  • 142.Perez-Galan P, Roue G, Villamor N, Campo E, Colomer D. The BH3-mimetic GX15-070 synergizes with bortezomib in mantle cell lymphoma by enhancing Noxa-mediated activation of Bak. Blood. 2007;109:4441–4449. doi: 10.1182/blood-2006-07-034173. [DOI] [PubMed] [Google Scholar]

Articles from Current Genomics are provided here courtesy of Bentham Science Publishers

RESOURCES