Abstract
For advanced prostate cancer (CaP), the progression of tumors to the state of chemoresistance and paucity of knowledge about the mechanism of chemoresistance are major stumbling blocks in the management of this disease. Here, we provide compelling evidence that BMI1 polycomb group protein and a stem cell factor plays a crucial role in determining the fate of tumors vis-à-vis chemotherapy. We show that progressive increase in the levels of BMI1 occurs during the progression of CaP disease in humans. We show that BMI1-rich tumor cells are non-responsive to chemotherapy whereas BMI1-silenced tumor cells are responsive to therapy. By employing microarray, ChIP, immunoblot and Luciferase reporter assays, we identified a unique mechanism through which BMI1 rescues tumor cells from chemotherapy. We found that BMI1 regulates (i) activity of TCF4 transcriptional factor and (ii) binding of TCF4 to the promoter region of anti-apoptotic BCL2 gene. Notably, an increased TCF4 occupancy on BCL2 gene was observed in prostatic tissues exhibiting high BMI1 levels. Using tumor cells other than CaP, we also showed that regulation of TCF4-mediated BCL2 by BMI1 is universal. It is noteworthy that forced expression of BMI1 was observed to drive normal cells to hyperproliferative mode. We show that targeting BMI1 improves the outcome of docetaxel therapy in animal models bearing chemoresistant prostatic tumors. We suggest that BMI1 could be exploited as a potential molecular target for therapeutics to treat chemoresistant tumors.
Highlights
According to American Cancer Society, an estimated 241,740 new cases of prostate cancer (CaP) were diagnosed and 28,170 CaP patients were projected to die in the year 2012 in USA alone [1]
Recent studies showed that dysregulation of BMI1 play a crucial role in epithelial mesenchymal transition, cell proliferation, senescence and self-renewability of several human cancers [11,16,29]
It is speculated that inability of tumor cells to undergo apoptosis in response to chemotherapy results in a selective advantage for such cells to become more aggressive compared to chemoresponsive cells [11]
Summary
According to American Cancer Society, an estimated 241,740 new cases of prostate cancer (CaP) were diagnosed and 28,170 CaP patients were projected to die in the year 2012 in USA alone [1]. Castration is a common treatment option for metastatic CaP, it does not significantly prolong the survival of patients and majority of these patients progress to castration-resistant prostate cancer (CRPC). A treatment option for CRPC is cytotoxic chemotherapy; chemotherapy improves overall survival in such patients by only a median of 2.9 months [6,7]. CRPC patients typically show rapid progression and develop chemoresistant disease [8,9,10]. Emergence of chemoresistance is considered a major hurdle in the management of CaP. The dismal outcome of the management of chemoresistant CRPC disease could be associated to the lack of knowledge about the molecular mechanism involved in the development of chemoresistant disease
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