Abstract
Kaposi’s sarcoma-associated herpesvirus (KSHV) is the etiologic agent of several human cancers, including primary effusion lymphoma (PEL), usually seen in immunocompromised patients while lack of effective therapeutic options. Interleukin-1 (IL-1) family is a major mediator for inflammatory responses and has functional role in both innate and adaptive immunity. We previously showed high activation of multiple IL-1 signaling molecules during KSHV latent and lytic stages, as well as in clinical samples from patients with KSHV-related malignancies. In the current study, we identified RP-54745, a potential antirheumatic compound as IL-1 inhibitor, effectively repressed KSHV + PEL cell growth through inducing tumor cell apoptosis. By using an established PEL xenograft model, we found that RP-54745 treatment suppressed tumor expansion in mice. Also, RP-54745 treatment significantly reduced hyperinflammation in tumor microenvironment including myeloid cells and neutrophils infiltration, as well as blocking IL-1 signaling molecules expression in vivo. In addition, our transcriptome analysis revealed novel cellular genes and mechanisms for anticancer activities of RP-54745. Taken together, our data indicate targeting IL-1 production and signaling may represent promising therapeutic strategies against these virus-associated diseases.
Keywords: IL-1, KSHV, lymphoma, PEL
1 |. Introduction
Kaposi’s sarcoma-associated herpesvirus (KSHV) is a principal causative agent of several cancers that arise in immunocompromised patients [1]. Among these cancers, primary effusion lymphoma (PEL) involves transformed B cells harboring KSHV and preferentially develops within the pleural or peritoneal cavities of immunosuppressed patients [2]. PEL is a rapidly progressing malignancy with a median survival time of only a few months, even with combination chemotherapy regimens such as CHOP or CHOP-like treatments [3]. Therefore, there is an urgent need for the development of effective therapies.
The interleukin-1 (IL-1) family is a major mediator of inflammatory responses and plays a functional role in both innate and adaptive immunity [4]. We previously demonstrated high activation of multiple IL-1 signaling molecules, such as IL-1α, IL-1β, type I IL-1 receptor (IL1R1), and IL-1 receptor accessory protein (IL1RAP), during both the latent and lytic stages of KSHV infection, as well as in clinical samples from patients with KSHV-related malignancies [5, 6]. Direct knockdown of these molecules, particularly IL1R1 and IL1RAP, was able to reduce the survival and growth of KSHV + PEL cells. Other studies have also shown that KSHV infection or its viral proteins induce IL-1 production from various host cell types [7, 8]. However, there is a lack of studies focused on the development of IL-1-targeted therapies for KSHV-related malignancies.
In the present study, we identified the IL-1 inhibitor RP-54745, which effectively suppressed KSHV + PEL cell growth by inducing tumor cell apoptosis. Additionally, we found that RP-54745 treatment reduced tumor expansion in xenografted mouse models, including a reduction in hyperinflammation in the tumor microenvironment, through interference with IL-1 production and signaling in vivo. Moreover, our transcriptomic analysis revealed novel cellular genes and mechanisms underlying the anticancer activities of RP-54745.
2 |. Materials and Methods
2.1 |. Cell Culture and Reagents
KSHV + PEL cell line BCBL-1 was kindly provided by Dr. Dean Kedes (University of Virginia) and cultured in RPMI 1640 media with supplemented with 10% fetal bovine serum (FBS), 10 mM HEPES, 100 U/mL penicillin, 100 μg/mL streptomycin, 2 mM l-glutamine, 0.05 mM β-mercaptoethanol, and 0.02% (wt/vol) sodium bicarbonate. RP-54745 and AF12198 were purchased from MedChemExpress. The JSC-1 and BL-41 cell lines were purchased from American Type Culture Collection (ATCC), and cultured as recommended by the manufacturer.
2.2 |. Cell Proliferation and Apoptosis Assays
Cell proliferation was assessed using the WST-1 Assay (Roche). After treatment, 10 μL/well of WST-1 reagent was added to 96-well plates and incubated for 3 h at 37°C in 5% CO2. Absorbance at 490 nm was measured using a microplate reader. Flow cytometry with the FITC-Annexin V/propidium iodide (PI) Apoptosis Detection Kit I (BD Pharmingen) was employed for quantitative apoptosis assessment, analyzed on a FACS Calibur 4-color flow cytometer (BD Bioscience).
2.3 |. Immunoblotting
Total cell lysates (30 μg) were resolved by 10% sodium dodecyl sulfate-polyacrylamide gel electrophoresis, transferred to nitrocellulose membranes, and incubated with 100–200 μg/mL of antibodies for Cleaved Caspase 3 and 9, Bax, Bcl-2 (Cell Signaling). β-Actin served as the loading control (Cell Signaling). Immunoreactive bands were identified using an enhanced chemiluminescence reaction (Perkin-Elmer) and visualized by autoradiography.
2.4 |. Quantitative Real-Time Polymerase Chain Reaction (RT-qPCR)
Total RNA was isolated using the RNeasy Mini kit (Qiagen), and cDNA was synthesized using a SuperScript III First-Strand Synthesis SuperMix Kit (Invitrogen). Primers used for amplification of target genes were described elsewhere [5, 9]. Amplification was carried out using an iCycler IQ Real-Time PCR Detection System, and cycle threshold (Ct) values were tabulated in duplicate for each gene of interest in each experiment. “No template” (water) controls were used to ensure minimal background contamination. Using mean Ct values tabulated for each gene, and paired Ct values for β-actin as a loading control, fold changes for experimental groups relative to assigned controls were calculated using automated iQ5 2.0 software (Bio-rad).
2.5 |. PEL Xenograft Model
For PEL xenograft model, NOD/SCID mice, 6–8-week old, male (Jackson Laboratory), 1 × 107 BCBL-1 cells in 200 μL RMPI-1640 without FBS were injected intraperitoneally and then mice were randomized into treatment groups of five mice as described previously [9]. After 72 h, mice were injected intraperitoneally with 5.0 mg/kg of RP-54745 or vehicle (n = 5 per group), once daily, 3 days per week, and weights were recorded weekly. The average animal weight gain during the 4-week treatment period among different groups were compared. All protocols were approved by the University of Arkansas for Medical Sciences Animal Care and Use Committee in accordance with national guidelines.
2.6 |. Immunohistochemistry
Formalin-fixed, paraffin-embedded tissues were microtome-sectioned to a thickness of 4 μm, placed on electromagnetically charged slides (Fisher Scientific). Immunohistochemistry was performed as described previously [10]. The antibodies for CD11b, Ly6G, IL-1β, IL1R1, IL1RAP, and MT2A were purchased from Abcam and used as recommended by the manufacturer. Images were collected using an Olympus BX61 microscope equipped with a high-resolution DP72 camera and CellSense image capture software.
2.7 |. RNA-Sequencing and Enrichment Analysis
RNA-Sequencing of triplicate samples was performed by BGI Americas Corporation using their unique DNBSEQ sequencing technology. The completed RNA-Sequencing data was submitted to NCBI Sequence Read Archive (SRA# PRJNA1188518). Raw sequencing reads were analyzed using the RSEM software (version 1.3.0; human GRCh38 genome sequence and annotation), and gene expression was quantified as previously described [11]. The EBSeq software was utilized to call differentially expressed genes that were statistically significant using a false discovery rate (FDR) less than 0.05. Differentially expressed genes between RP-54745- and vehicle-treated tumor cells were used as input for the GO_enrichment and KEGG pathways analyses.
2.8 |. Statistical Analysis
Significance for differences between experimental and control groups was determined using the two-tailed Student’s t-test (Excel 2016).
3 |. Results
3.1 |. RP-54745 Treatment Inhibits PEL Cell Growth
RP-54745, an amino-dithiole-one antirheumatic compound, was originally identified for its ability to inhibit stimulated macrophages by interfering with the hexose monophosphate (HMP) pathway, the exocytosis of lysosomal enzymes, and the production of IL-1 [12]. Its IL-1 inhibitory effect has also been verified ex vivo and in vivo [13]. In this study, we found that RP-54745 treatment effectively reduced the growth of PEL cell lines, BCBL-1 and JSC-1, in a dose-dependent manner (Figure 1A and Supporting Information: S1). Additionally, RP-54745 treatment significantly downregulated IL1R1 transcripts, while moderately reducing IL-1β and IL1RAP transcripts (Figure 1B). Flow cytometry analysis revealed that RP-54745 treatment significantly induced apoptosis in BCBL-1 cells (Figure 2A,B), which was further confirmed by the increased cleavage of Caspases-3 and −9, two key apoptosis markers (Figure 2C). RP-54745 treatment also affected other apoptosis-related proteins, including an increase in Bax expression and a decrease in Bcl-2 expression. In contrast, we found that RP-54745 treatment had minimal impact on viral gene expression, including both latent and lytic genes in BCBL-1 cells as measured by RT-qPCR (Figure 3), suggesting that the induced apoptosis was not due to lytic reactivation. Furthermore, another recently reported IL-1 inhibitor, AF12198 [14], was also found to reduce PEL cell growth by inducing tumor cell apoptosis (Supporting Information: Figure S2), although its effects were less pronounced than those of RP-54745. Both compounds showed much less inhibition of growth in the KSHV-negative lymphoma cell line BL-41 (Supporting Information: Figure S3). Based on these findings, we chose to focus on RP-54745 in subsequent experiments.
FIGURE 1 |.
RP-54745 treatment inhibits PEL cell growth. (A) BCBL-1 cells were treated with indicated concentrations of RP-54745 for 48 h, then cell viability was determined using WST-1 assays (Roche). (B) Gene expression was detected and compared by using RT-qPCR (RP-54745 at 0.5 μM for 48 h). Error bars represent the SD for three independent experiments. *p < 0.05; **p < 0.01. PEL, primary effusion lymphoma; RT-qPCR, quantitative real-time polymerase chain reaction; SD, standard deviation.
FIGURE 2 |.
RP-54745 treatment induces PEL cell apoptosis. (A, B) BCBL-1 was treated with indicated concentrations of RP-54745 or vehicle for 24 h, then the cell apoptosis was quantified using flow cytometry analysis. Error bars represent SD for three independent experiments, **p < 0.01. (C) The protein expression was measured using western blot. PEL, primary effusion lymphoma; SD, standard deviation.
FIGURE 3 |.
RP-54745 treatment slightly affects viral gene expression from PEL cells. BCBL-1 was treated with indicated concentrations of RP-54745 or vehicle for 24 h, then gene expression was detected and compared by using RT-qPCR. Error bars represent the SD for three independent experiments. PEL, primary effusion lymphoma; RT-qPCR, quantitative real-time polymerase chain reaction; SD, standard deviation.
3.2 |. RP-54745 Treatment Represses PEL Tumor Progression In Vivo
Next, we evaluated the efficacy of RP-54745 in an established PEL xenograft model, in which BCBL-1 cells were intraperitoneally injected into NOD/SCID mice [9]. RP-54745 (or vehicle) was administered intraperitoneally within 72 h of BCBL-1 injection, and treatment continued for 4 weeks (Figure 4A). RP-54745 treatment effectively suppressed PEL tumor progression, including reducing ascites formation and splenomegaly over this period (Figure 4B,C). Histologic analysis of splenic tissues from vehicle-treated mice showed significant tumor infiltration and disordered splenic architecture. In contrast, splenic tissues from RP-54745-treated mice exhibited nearly normal splenic architecture (Figure 4D). Additionally, we found that RP-54745 treatment significantly reduced the infiltration of immune cells in the tumor microenvironment, including myeloid cells (CD11b +) and neutrophils (Ly6G +) (Figure 5A). RP-54745 treatment also reduced the expression of IL-1 signaling molecules, such as IL-1β, IL1R1, and IL1RAP, in the splenic tissues of treated mice (Figure 5B), with a particularly sharp reduction in IL1R1 expression.
FIGURE 4 |.
RP-54745 treatment represses PEL tumor progression in vivo. (A) NOD/SCID mice were injected IP with 5.0 mg/kg of RP-54745 or vehicle (n = 5 per group), once daily, 3 days per week, and weights were recorded weekly. The average animal weight gain during the 4-week treatment period among different groups were compared. (B–D) After the mice were killed, the ascites and spleens were collected for comparison as well as histologic analysis. **p < 0.01. PEL, primary effusion lymphoma.
FIGURE 5 |.
RP-54745 treatment reduces inflammation in tumor microenvironment through interfering with IL-1 production in vivo. (A and B) The expression of CD11b (myeloid cells marker), Ly6G (neutrophils marker), IL-1β, IL1R1, and IL1RAP in splenic tissues collected from vehicle- or RP-54745-treated PEL xenograft mice were detected and compared using immunohistochemistry staining. IL, interleukin.
3.3 |. Transcriptomic Analysis of Gene Profiling in PEL Cells Altered by RP-54745
To explore the global cellular changes induced by RP-54745, we compared the gene profiles of vehicle- and RP-54745-treated BCBL-1 cells using RNA-Sequencing. Volcano plots revealed a scatter of genes that were significantly upregulated or downregulated (FDR < 0.05) in RP-54745-treated BCBL-1 cells (Figure 6A). The top 20 significantly upregulated and downregulated genes are listed in Tables 1 and 2, respectively. Gene Ontology (GO) enrichment analysis of these differentially expressed genes identified several major functional categories potentially involved in RP-54745’s effects. The biological process module analysis indicated that many of these genes were involved in functions critical for the regulation of the cell cycle, sterol biosynthesis, cholesterol biosynthesis, and mitotic sister chromatid segregation, among others (Figure 6B). The Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis revealed that RP-54745 treatment impacted pathways related to steroid biosynthesis, the cell cycle, lysosomes, and toxoplasmosis (Figure 6C).
FIGURE 6 |.
Transcriptome analysis of RP-54745-treated KSHV+ tumor cells. (A) RNA-Sequencing was used to investigate changes in the transcriptome between RP-54745- and vehicle-treated BCBL-1 cells. The significantly altered genes (FDR < 0.05) were shown in the Volcano plot panels. (B, C) The GO_enrichment (Biological process module) and KEGG pathways analysis of the significantly altered genes in RP-54745-treated BCBL-1 cells. GO, Gene Ontology; KEGG, Kyoto Encyclopedia of Genes and Genomes.
TABLE 1 |.
The top 20 candidate genes upregulated within RP-54745 treated BCBL-1 cells.
| Gene | FC | FDR | Description |
|---|---|---|---|
| ABHD16B | 95.99374 | 1.11E-17 | Abhydrolase domain containing 16B |
| PCDHGC3 | 56.22619 | 0.005338 | Protocadherin gamma subfamily C, 3 |
| TNFRSF6B | 43.29763 | 0.009072 | TNF receptor superfamily member 6b |
| MT2A | 16.37899 | 2.44E-05 | Metallothionein 2A |
| ASS1 | 13.42917 | 7.24E-12 | Argininosuccinate synthase 1 |
| HIST2H2AA4 | 11.61791 | 0.021439 | H2A clustered histone 19 |
| IFIT3 | 10.50935 | 1.11E-17 | Interferon-induced protein with tetratricopeptide repeats 3 |
| MT1F | 9.102112 | 2.31E-06 | Metallothionein 1F |
| DDX60 | 8.935408 | 0.001169 | DExD/H-box helicase 60 |
| KCNE1L | 6.637988 | 0.044688 | Potassium voltage-gated channel subfamily E regulatory subunit 5 |
| BEST1 | 5.766101 | 0.002499 | Bestrophin 1 |
| HERC5 | 5.719484 | 0.001533 | HECT and RLD domain containing E3 ubiquitin protein ligase 5 |
| HSPA6 | 5.242594 | 8.91E-09 | Heat shock protein family A (Hsp70) member 6 |
| CYP4F11 | 4.804224 | 9.82E-06 | Cytochrome P450 family 4 subfamily F member 11 |
| EGR1 | 3.761246 | 0.006388 | Early growth response 1 |
| VNN2 | 3.648605 | 1.97E-05 | Vanin 2 |
| LY96 | 3.445931 | 8.31E-07 | Lymphocyte antigen 96 |
| RENBP | 3.439592 | 1.61E-09 | Renin binding protein |
| CELF6 | 3.224402 | 1.11E-17 | CUGBP Elav-like family member 6 |
| SLC22A18 | 3.089029 | 0.012475 | Solute carrier family 22 member 18 |
Abbreviations: FC, fold change; FDR, false discovery rate.
TABLE 2 |.
The top 20 candidate genes downregulated within RP-54745 treated BCBL-1 cells.
| Gene | FC | FDR | Description |
|---|---|---|---|
| SULT1A4 | 0.216249 | 1.11E-17 | Sulfotransferase family 1A member 4 |
| GPRC5D | 0.269935 | 1.11E-17 | G protein-coupled receptor class C group 5 member D |
| PIK3R2 | 0.274117 | 0.007767 | Phosphoinositide-3-kinase regulatory subunit 2 |
| CHAC1 | 0.281342 | 1.11E-17 | ChaC glutathione specific gamma-glutamylcyclotransferase 1 |
| IGSF9 | 0.332362 | 0.002846 | Immunoglobulin superfamily member 9 |
| CNTF | 0.336004 | 0.005166 | Ciliary neurotrophic factor |
| SLC24A2 | 0.337784 | 0.012507 | Solute carrier family 24 member 4 |
| AHNAK | 0.339459 | 0.001922 | AHNAK nucleoprotein |
| GABRR2 | 0.340736 | 0.020603 | Gamma-aminobutyric acid type A receptor subunit rho2 |
| PDGFRA | 0.346682 | 1.11E-17 | Platelet-derived growth factor receptor alpha |
| SETBP1 | 0.352566 | 9.33E-08 | SET binding protein 1 |
| HEG1 | 0.352907 | 1.84E-12 | Heart development protein with EGF like domains 1 |
| RAPH1 | 0.361697 | 2.43E-05 | Ras association (RalGDS/AF-6) and pleckstrin homology domains 1 |
| DSP | 0.362143 | 1.61E-07 | Dentin sialophosphoprotein |
| ITPR2 | 0.363138 | 2.99E-05 | Inositol 1,4,5-trisphosphate receptor type 2 |
| MKI67 | 0.365064 | 0.005967 | Marker of proliferation Ki-67 |
| CCDC39 | 0.366239 | 0.000315 | Coiled-coil domain 39 molecular ruler complex subunit |
| TET1 | 0.371561 | 0.000377 | Tet methylcytosine dioxygenase 1 |
| SAMD9 | 0.379754 | 7.50E-05 | Sterile alpha motif domain containing 9 |
| MYH11 | 0.383836 | 0.001842 | Myosin heavy chain 11 |
Abbreviations: FC, fold change; FDR, false discovery rate.
We next focused on one candidate gene, metallothionein 2 A (MT2A), which was significantly upregulated in RP-54745-treated BCBL-1 cells (Table 1). Metallothioneins (MTs) are a group of small cysteine-rich proteins, consisting of four main gene subfamilies (MT1, MT2A, MT3, and MT4) in humans [15]. Previous studies have shown that MTs, including MT2A, are involved in various biological processes such as oxidation, cellular proliferation, differentiation, invasion, and carcinogenesis [16, 17]. We confirmed that RP-54745 treatment dramatically increased MT2A expression in the splenic tissues of treated mice (Figure 7), which is consistent with the transcriptomic analysis results in vitro and suggests a potential contribution of MT2A to the anticancer activity of RP-54745.
FIGURE 7 |.
The upregulation of MT2A expression in splenic tissues from RP-54745-treated mice. The expression of MT2A in splenic tissues collected from vehicle- or RP-54745-treated PEL xenograft mice was detected and compared using immunohistochemistry staining. PEL, primary effusion lymphoma.
4 |. Discussion
Inflammation is a hallmark of KSHV-associated diseases, which are often seen in immunocompromised patients who may also have concurrent infections [18]. Elevated levels of circulating cytokines, particularly IL-6 and IL-10, have been linked to worse outcomes in PEL patients [19]. One interesting study reported that Pseudomonas aeruginosa, an opportunistic bacterium commonly found in AIDS patients, could stimulate inflammation and enhance KSHV-induced cell proliferation and cellular transformation [20]. Another study demonstrated that the commonly used anti-inflammatory agent dexamethasone blocked KSHV-induced hyperinflammation and tumorigenesis by activating glucocorticoid receptor signaling to suppress IL-1α and induce the IL-1 receptor antagonist (IL-1Ra) [21]. These and other studies highlight the critical role of the inflammatory tumor microenvironment in the survival of KSHV+ tumor cells and the development of KSHV-related malignancies.
We have previously shown that multiple IL-1 signaling molecules are highly activated during both the latent and lytic stages of KSHV infection, as well as in clinical samples from patients with KSHV-related malignancies [5]. In the current study, we report for the first time that RP-54745, a potential IL-1 inhibitor, effectively suppressed KSHV + PEL cell growth and tumor expansion both in vitro and in vivo. Notably, even in immunocompromised PEL mouse models (NOD/SCID mice, which are deficient in T and B cells), we observed hyperinflammation in the tumor microenvironment, as indicated by an abundance of infiltrating myeloid cells and neutrophils in splenic tissues. In contrast, RP-54745 treatment significantly reduced the infiltration of these inflammatory cells and blocked IL-1 signaling molecules, particularly IL1R1, in vivo (Figure 5). However, at the end of the 4-week treatment period, we still observed residual ascites in RP-54745-treated mice, and tumor growth remained slow (Figure 4). These findings suggest that IL-1 inhibitors, or other anti-inflammatory agents, may need to be combined with additional therapies to achieve better outcomes, such as complete tumor regression.
By using RNA-sequencing analyses, we identified a number of candidate genes that were significantly changed in RP-54745 treated BCBL-1, indicating that RP-54745 appears to have multiple effects on PEL cells. One of these candidate genes, MT2A, was highly upregulated in RP-54745-treated BCBL-1 cells and was also confirmed to be elevated in splenic tissues from RP-54745-treated mice. Pan et al. reported that MT2A exhibited tumor-suppressive activity by inhibiting nuclear transcription factor κB (NF-κB) signaling in gastric cancer [22]. Another recent study demonstrated that MT2A acted as an antioxidant and tumor suppressor in human bladder carcinoma cells [23]. This study found that MT2A overexpression not only downregulated endogenous reactive oxygen species (ROS) but also blocked ROS induced by H2O2. Knockdown of MT2A increased the invasion and growth of bladder carcinoma cells both in vitro and in vivo. However, the potential relationship between MT2A and IL-1 signaling, as well as its functional role in KSHV+ tumor cell pathogenesis, remains unclear and warrants further investigation. Nonetheless, our data suggest that targeting IL-1 production and signaling could represent a promising therapeutic strategy for treating these virus-associated diseases.
Supplementary Material
Supporting Information
Additional supporting information can be found online in the Supporting Information section.
Acknowledgments
This work was supported by NIH R03DE031978, R21AI186566, and the Arkansas Bioscience Institute, the major research component of the Arkansas Tobacco Settlement Proceeds Act of 2000. Z.L. was supported by a National Cancer Institute grant R01CA261258, a National Institute of General Medical Sciences COBRE grant P20GM121288, a U.S.-Japan Cooperative Medical Sciences Program Collaborative Award from the National Institute of Allergy and Infectious Diseases and CRDF Global (grant number DAA3-19-65602-1), a Ladies Leukemia League research grant, a Tulane school of medicine faculty research pilot grant, and a Carol Lavin Bernick faculty grant. L.H. was supported by NIH grants (R21AI175738, R01AI184960). Funding sources had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Funding:
The study was supported by the National Institutes of Health (R03DE031978, R21AI186566, R21AI175738, and R01AI184960), National Cancer Institute (R01CA261258), National Institute of General Medical Sciences COBRE (P20GM121288), U.S.-Japan Cooperative Medical Sciences Program Collaborative Award from the National Institute of Allergy and Infectious Diseases and CRDF Global (DAA3-19-65602-1).
Footnotes
Conflicts of Interest
The authors declare no conflicts of interest.
Data Availability Statement
All the data shown in this article are available from the corresponding authors upon reasonable request.
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Associated Data
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Supplementary Materials
Data Availability Statement
All the data shown in this article are available from the corresponding authors upon reasonable request.