B-cell leukemia 3 (Bcl-3) is a member of the inhibitor of κB family, which regulates a wide range of biological processes by functioning as a transcriptional activator or as a repressor of target genes. As high levels of Bcl-3 expression and activation have been detected in different types of human cancer, Bcl-3 has been labeled a proto-oncogene. Our study uncovered a markedly upregulated Bcl-3 expression in human prostate cancer (PCa), where inflammatory cell infiltration was observed. Elevated Bcl-3 expression in PCa was dependent on the proinflammatory cytokine interleukin-6-mediated STAT3 activation. Microarray analyses, using Bcl-3 knockdown in PCa cells, identified the inhibitor of DNA-binding (Id) family of helix-loop-helix proteins as potential Bcl-3-regulated genes. Bcl-3 knockdown reduced the abundance of Id-1 and Id-2 proteins and boosted PCa cells to be more receptive to undergoing apoptosis following treatment with anticancer drug. Our data imply that inactivation of Bcl-3 may lead to sensitization of cancer cells to chemotherapeutic drug-induced apoptosis, thus suggesting a potential therapeutic strategy in PCa treatment.
Prostate cancer (PCa) is the second most frequently diagnosed as well as the most common cancer in men in Europe. Being the leading cause of cancer among men worldwide, PCa is, after lung cancer, the second most common cause of death from cancer in men in the United States.1, 2 The number of afflicted men is rapidly growing along with the population of males over the age of 50 expanding worldwide. PCa is a heterogeneous disease, the etiology of which appears to be related to a complex range of risk factors, including lifestyle patterns, genetic factors and epigenetic modifications.1
Approximately 20% of all human cancers in adults result from chronic inflammation,3 triggered by infectious agents or by exposure to various environmental factors. Evidence is now emerging that inflammation is crucial for the etiology of PCa. Although the cause of prostatic inflammation is unclear, infection, hormones, urine reflux and dietary habits have been suggested as potential triggers of the initial igniting event.4 The prostate tumor microenvironment, which consists of multiple cell types and soluble factors such as cytokines, is one of the important factors influencing the establishment and progression of PCa.5 Genetic epidemiology studies have implicated several polymorphic variant alleles of genes encoding oxidant defense enzymes as well as of genes encoding inflammatory cytokines such as interleukin-6 (IL-6), in PCa-risk groups. A major target of nonsteroidal anti-inflammatory drugs, cyclooxygenase-2, appears to be expressed in inflammatory cells in the prostate as well as in proliferative inflammatory atrophy lesions, a suspected PCa precursor,6 and proliferating prostatic epithelial cells are often located near activated inflammatory cells.7 In a chronic inflammatory state, epithelial damage and regeneration repeatedly occur in a setting of exposure to reactive oxygen and nitrogen species prompted by inflammatory cells, increasing the propensity for neoplastic transformation.8
Recently, different studies linked IL-6 expression and signaling to prostate tumorigenesis. Initially, high levels of IL-6 were measured in supernatants from advanced PCa cells and in specimens obtained from patients with prostate diseases.9 In benign prostate hyperplasia, IL-6 expression has been detected in the basal cells, while the presence of IL-6 receptors in tumor tissues indicated that signaling pathways of the cytokine are operative in most patients with malignant prostate disease.10 IL-6 is as a rule communicating by activating Janus kinases as well as transcription factors of the signal transducer and activator of transcription (STAT) family, including STAT1 and STAT3.11 Prolonged culturing of PCa cell lines LNCaP in a medium supplemented with IL-6 (LNCaP-IL-6+), acquired a growth advantage by expression of the molecules, driving the cell cycle progression as well as the constitutive activity of mitogen-activated protein kinases.12 In vivo, using the xenograft model, the anti-IL-6 chimeric monoclonal antibody (Siltuximab or CNTO 328) delayed the tumor progression of PCa cells.13 Beside proliferation, IL-6 expression has been proven to inhibit apoptosis in androgen-negative PCa cells,14 and IL-6 has consequently been suggested to have a crucial role in resistance to chemotherapy involving apoptotic cell death.15 However, the molecular mechanisms by which IL-6 promotes tumor cell survival and protection against chemotherapeutic drug-induced apoptosis in PCa, remain unclear.
The first identification of B-cell leukemia 3 (Bcl-3) was achieved by performing molecular cloning of the breakpoint of the t(14;19) chromosomal translocation from a subset of human B-cell chronic lymphocytic leukemia.16 Overexpression of Bcl-3 brings about an impairment of the regulatory mechanisms of downstream target genes, predominantly not yet unveiled. High Bcl-3 expression and activation has been detected in breast cancer, nasopharyngeal carcinoma and melanoma as well as in different types of skin cancer, such as basal cell carcinoma and cylindroma.17, 18, 19, 20, 21 Furthermore, Bcl-3 expression and activation has been connected with increased cellular proliferation or survival, dependent on the tissue and type of stimuli.18, 19, 20, 22, 23, 24 Recently, the transcriptional repressor function of Bcl-3 in regulating immune responses as well as the development and activation of immune cells has been established. Bcl-3 was shown to suppress the activation of tumor necrosis factor-α promoter in macrophages upon lipopolysaccharide stimulation.25, 26 The repressor function of Bcl-3 is mediated through its direct association with C-terminal-binding protein, which is necessary for the oncogenic potential of Bcl-3 by preventing cell apoptosis upon ultraviolet induction.27
This study investigated the levels of Bcl-3 in PCa cells when exposed to IL-6 stimulation. We also studied possible regulation of the inhibitor of DNA-binding (Id) family of helix-loop-helix proteins by Bcl-3 to detect if there is any effect on apoptosis in prostate tumor cells upon treatment with anticancer drugs.
Results and discussion
When exploring the function of Bcl-3 in PCa, initially evaluating the Bcl-3 protein expression in a human PCa tissue microarray (details in Supplementary Methods), we found a strong upregulation of Bcl-3 expression in tumors where the recruitment of inflammatory cells was observed (Figures 1a and b and Supplementary Table 1), as well as in PCa compared with benign prostatic epithelium (Supplementary Figure 1). Furthermore, the analyses of PCa cell lines manifested that DU145 and LNCaP-IL-6+ showed the highest expression levels of Bcl-3, compared with other cell lines (Figure 2a). As Bcl-3 has been suggested to be an IL-6 target gene28 and LNCaP-IL-6+ exhibits elevated levels of Bcl-3 compared with LNCaP cells (Figure 2a), we speculated whether IL-6 may regulate the levels of Bcl-3 in PCa cells. Stimulation of different PCa cell lines (25 ng/ml IL-6 for 24 h) resulted in an upregulation of Bcl-3 in all cell lines tested, except in PC-3 cells (Figure 2b). In addition, IL-6 promoted upregulation of Bcl-3 expression in a time-dependent manner at the levels of protein and mRNA (Figures 2c and d).
IL-6 belongs to a larger family of cytokines signaling through a common receptor, gp130, which results in activation of the associated Janus kinases as well as recruitment and activation of the STAT1 and STAT3 transcription factors.29 Cell lysate from non-stimulated or IL-6-stimulated PCa cell lines, probed using a phospho-STAT3 (pSTAT3) antibody, resulted in IL-6 promoting phosphorylation of STAT3 in all cell lines, except for PC-3 cells (Figure 2b), which also expressed very low levels of total STAT3 protein (Figure 2b). The subsequent investigation of the Bcl-3 levels in the presence of two different STAT3 inhibitors, WP1066 and Stattic3, revealed interestingly that in the presence of STAT3 inhibitors, all PCa cell lines displayed a reduced Bcl-3 expression (Figure 2e). Consistent with this result, cells treated with small interfering RNA targeting STAT3 had lower levels of Bcl-3 than those treated with control small interfering RNA (Figure 2f). Our results suggest that an IL-6-mediated upregulation of Bcl-3 is mediated via a Janus kinase/STAT3 signaling pathway. We have previously demonstrated that in keratinocytes or melanocytes, ultraviolet-B light facilitates nuclear translocation of Bcl-3.19, 20 In this experiment, we found that IL-6-stimulated Bcl-3 nuclear translocation in LNCaP, LNCaP+IL-6 and DU145 cells (Figure 2g). Furthermore, pretreatment of LNCaP cells with WP1066 before IL-6 stimulation prevented nuclear translocation of Bcl-3 (Figure 2h). As expected, IL-6 stimulation of PC-3 cells did not facilitate nuclear translocation of Bcl-3 (Figure 2g). Our finding suggests that in addition to upregulation of Bcl-3, IL-6 promotes nuclear translocation of Bcl-3.
Of the four different stable single clones we established, having 40–90% Bcl-3 knockdown (details in Supplementary Methods), DU shBcl-3#1 had the greatest knockdown, whereas the three others (DU shBcl-3#2, DU shBcl-3#3 and DU shBcl-3#4) exhibited smaller reductions of Bcl-3 (Figure 3a). Single clones (DU shControl#1 and DU shControl#2) with control shRNA showed no differences in Bcl-3 levels compared with parental DU145 cells (Figure 3a). Analyzing the requirements of cellular adaptive processes revealed no differences in proliferation, adhesion and cell migration between Bcl-3 knockdown and control cells (Supplementary Figures 2–4). Surprisingly, after treatment with anticancer drugs staurosporine, etoposide or paclitaxel, Bcl-3 knockdown cells were more amenable to undergo apoptosis compared with control cells (Figure 3b and Supplementary Figure 5).
The microarray analyses (see Supplementary Methods) of the effects of Bcl-3 knockdown on patterns of global gene expression in PCa cells, using isolated total RNA, disclosed that 182 genes were downregulated and 33 genes upregulated in the knockdown cells, compared with the control cells (complete list in Supplementary Table 2). Among the 20 genes most effectively downregulated, the inhibitor of DNA-binding (Id) family of helix-loop-helix proteins was present (Supplementary Table 3). This finding was confirmed by the real-time PCR and the western blot analysis of Id proteins (Id-1 and Id-2; Figures 3c and d), where we also observe that another clone of Bcl-3 knockdown cells (DU shBcl-3#2) displayed a similar effect (Figure 3c). Furthermore, stimulation with IL-6 (Figure 3e) or overexpression of Bcl-3 (Figure 3f) in LNCaP cells increased Id-1 and Id-2 mRNA levels and protected the cells from etoposide cytotoxicity (Figure 3g). The analysis of the activity level of Id-2 promoter luciferase revealed that while Bcl-3 knockdown cells (DU shBcl-3#1 and DU shBcl-3#2) reduced Id-2 promoter activity, the control cells were unaffected (Figure 3h and Supplementary Figure 6). In addition, transient overexpression of Bcl-3 in knockdown cells (DU shBcl-3#1), elevated Id-2 promoter activity compared with MOCK-transfected cells (Figure 3i). The chromatin immunoprecipitation assays, using DU145 cells, uncovered which nuclear factor-κB-binding sites in the Id-1 and Id-2 promoters that Bcl-3 is able to bind. Bcl-3 was recruited to the Id-1 promoter at position +787 and to the Id-2 promoter at position +474, but not to the Id-2 promoter at position 3901 (Figure 3j). In addition, Id-2 downregulated DU145 cells (Supplementary Figure 7) showed to be more sensitive to etoposide-mediated apoptosis compared with control cells (Supplementary Figure 8). These results indicate that upon IL-6 stimulation, Bcl-3 recruits to the promoters of Id-1 and Id-2 genes in the PCa cells, thus initiating the expression of these proteins and preventing apoptosis induced by chemotherapeutic drugs.
The weight of Bcl-3 knockdown tumors following subcutaneous implantation of 7.0 × 106 cells in nude mice (Figure 4a and Supplementary Methods) were markedly reduced than those of control (Figure 4b), confirming the effects of Bcl-3 on PCa cell growth in vivo. Notably, although the number of proliferating cells did not differ (Figure 4c), immunohistochemistry using cleaved caspase 3 disclosed significant differences in the number of apoptotic cells (Figure 4d). In addition, the Id-1 expression in Bcl-3 knockdown tumor cells isolated from nude mice was reduced compared with the control cells (Figure 4e). The manual scoring of the 122 PCa tissue microarray cores allowed for a direct comparison of nuclear localization of staining for Bcl-3 protein as well as the intensity of the Id-1 protein staining (Supplementary Table 4). This comparison clearly demonstrated the impact of Bcl-3-mediated Id-1 expression levels in human prostate tumors, with a statistically significant correlation between nuclear localized Bcl-3 and reduced intensity of Id-1 protein expression (r=0.282, P=0.002; Spearman's rank correlation coefficient tests; Supplementary Table 4).
The role of Bcl-3 in the development and progression of PCa is to date unknown. Our findings indicate that Bcl-3 may be a vital regulator of PCa cell survival; nuclear translocation as well as the level of Bcl-3 was directly related to IL-6 and its downstream signaling pathway, including STAT3 activation. Nuclear Bcl-3 is generally used as a complex, with nuclear factor-κB family member p50 or p52 recruited to the promoter, for initiation of the transcription of target genes. It is important to note that p52 was recently shown to be upregulated in PCa and is able to promote cell growth by recruitment of p300 to the promoter of androgen receptor.30 However, in our system, we suggest that p52 recruits Bcl-3 to the promoter of Id proteins for protection against apoptosis. In addition, human PCa tissue sections stained with phospho-p52 held high p52 levels, correlated with an adverse prognosis. It was thus suggested that p52 may function as a predictor of an unfavorable PCa prognosis.31 Furthermore, it was shown recently that overexpression of p52 protected androgen-sensitive LNCaP cells from apoptotic cell death.32 Our present results extend these previous findings, implying that Bcl-3, in a complex with p52, has an important role in the genesis of PCa. This is of vital importance, as p52 binding to the promoter of a suspected gene alone function as a repressor, whereas p52 bound to Bcl-3 initiate transcription of the target gene.
Our study also uncovered a new mechanism in the Bcl-3-mediated IL-6 signaling pathway responsible for apoptosis resistance of PCa cells. This mechanism is based on the upregulation of the Id gene product by the transcriptional regulator Bcl-3, whose expression is activated by IL-6, thereby inducing resistance to treatment with anticancer drugs. An aberrant expression of the IL-6 gene along with an autocrine production of IL-6 in tumor cells has previously been linked to resistance of these cells to chemotherapy.13, 15 Bcl-3 belongs to the target genes of the IL-6 signaling pathway.33 Previous characterization of the role of Bcl-3 in cancer cell proliferation17, 19 has not conclusively elucidated its function in cell survival. IL-4 was shown to induce cell death via downregulation of Bcl-324 and induction of Bcl-3 by DNA damaging agents limited p53-mediated apoptosis.23 Furthermore, apoptotic stimuli-induced degradation of C-terminal-binding protein 1 was abolished by Bcl-3, which further promoted cell survival.22 In our study, we found that the IL-6-mediated anti-apoptotic effect of Bcl-3 was due to the transcription activation of Id proteins. This was achieved through direct recruitment of Bcl-3 to the Id-2 promoter and an increase in the Id-2 promoter activity. An elevated Bcl-3 expression was also correlated to the Id-1 expression in the human prostate tumors, whereas Bcl-3 knockdown reduced the Id-2 expression in prostate tumor cell lines. Id-1 was suggested to serve as a useful prognostic marker for PCa. Elevated expression of Id-1 was significantly correlated with shorter survival rates.34 Further, Id-1 overexpression in LNCap cells promoted a more aggressive phenotype of these cells including downregulation of prostate-specific antigen gene expression.35 The mechanisms responsible for the Ids anti-apoptotic effects are not clear. Id-1 and Id-2 proteins has been shown to be protective against apoptosis in different cell types and tissues.36, 37, 38, 39, 40 More specifically, in PCa, Id-1 promoted cell survival through activation of the nuclear factor-κB signaling pathway along with an inactivation of Id-1, resulted in an increased sensitivity to tumor necrosis factor-α-induced apoptosis.41 Further, inactivation or downregulation of Id-1 in PCa cells was shown to reduce cell survival upon treatment with anticancer agents.42, 43, 44, 45
In this study, we noted that knockdown of Bcl-3 in PCa cells, sensitized these cells to apoptosis upon treatment with staurosporin. In contrast, when Bcl-3 was upregulated via IL-6 stimulation, PCa cells were protected against cell death. Collectively, our findings suggest that inactivation of Bcl-3, leading to sensitization of PCa cells to chemotherapeutic drug-induced apoptosis, may be a potential therapeutic strategy.
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We thank Elise Nilsson for excellent technical assistance, Dr Zoran Culig (Innsbruck Medical University, Austria) for providing us the LNCaP-IL-6+ cells, Dr Takashi Tokino (Cancer Research Institute, Sapporo, Japan) for human Id-2 promoter luciferase reporter construct, Dr Roland M Schmid (Technical University Munich, Munich, Germany) for FLAG-Bcl-3 expression construct, Dr David Ulmert (Lund University, Lund, Sweden) for characterization of the human PCa tissue microarray and Dr Srinivas Veerla (SCIBLU, Lund University, Lund, Sweden) for microarray analysis and gene expression profiling. This work was supported by the Swedish Society for Medical Research, Swedish Cancer Foundation, Swedish Medical Research Council, Royal Physiographic Society in Lund, U-MAS Research Foundations, and funding from the European Research Council under the European Union's seventh framework program ERC grant agreement (260460 to RM).
The authors declare no conflict of interest.
Supplementary Information accompanies the paper on the Oncogene website
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Ahlqvist, K., Saamarthy, K., Syed Khaja, A. et al. Expression of Id proteins is regulated by the Bcl-3 proto-oncogene in prostate cancer. Oncogene 32, 1601–1608 (2013). https://doi.org/10.1038/onc.2012.175
- prostate cancer
- inhibitor of DNA binding (Id)
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