Functional significance of PIAS1 and BIRC5 in docetaxel resistant prostate cancer

Prostate cancer is the most commonly diagnosed cancer in men. After lung cancer, prostate cancer is the second leading cause of cancer-related mortality in men and is responsible for approximately 11% of all cancer deaths. Unfortunately, there is currently no curative treatment for men with locally advanced or widespread disease, although combination treatment with non-steroidal anti-androgens can delay cancer progression and relieve disease symptoms for 18-24 months. Despite castrate levels of circulating testosterone, the disease finally progresses to castration resistant prostate cancer (CRPC), for which a palliative systemic chemotherapy has been developed in the last years. The chemotherapeutic drug docetaxel (also called taxotere) is the current state of the art treatment for CRPC. However, clinical treatment with docetaxel often encounters a number of undesirable side effects. Moreover, many patients do not initially respond to docetaxel or acquire docetaxel resistance during treatment. Until now, little is known regarding molecular mechanisms underlying acquired docetaxel insensitivity in prostate cancer. To gain a greater insight into the molecular changes, which lead to or are associated with docetaxel insensitivity, the applicant has already generated and characterized docetaxel resistant prostate cancer cells. Preliminary data indicate significant upregulation of Protein inhibitor of activated STAT1 (PIAS1) and baculoviral IAP repeat containing 5 (BIRC5) in these docetaxel resistant cell lines. Thus, it is hypothesized that elevated PIAS1 and/or BIRC5 levels may be associated with decreased docetaxel sensitivity. Recent studies have also implicated dysregulation of specific microRNAs, like decreased expression of microRNA miR-34 with tumor development and chemotherapy resistance in breast and prostate cancer. This specific microRNA has also predicted binding sequences for PIAS1 and BIRC5. Therefore, elevated PIAS1 and BIRC5 levels may also be an indirect consequence of altered expression of specific microRNAs. Due to this evidence Dr. Puhr hypothesizes that an increased expression of PIAS1 and BIRC5 protein is at least in part responsible for docetaxel resistance and chemotherapy failure. The main aim of the proposed study is to identify the molecular mechanisms leading to upregulation of PIAS1 and BIRC5 during docetaxel resistance in vitro and to investigate whether their upregulation plays a role in the development of docetaxel resistance. To this end, the functional significance of increased PIAS1 and BIRC5 levels will be investigated both in vitro and in tissue specimens of prostate cancer patients. Moreover, it is planned to specifically inhibit PIAS1 and BIRC5 protein expression in vivo to determine whether targeting these proteins alone or in combination may represent a basis for improved prostate cancer therapy in the future.

Prostate cancer (PCa) is the most commonly diagnosed cancer in men and second leading cause of cancer-related death after lung cancer. Unfortunately, there is currently no curative treatment for men with metastatic castration resistant prostate cancer (CRPC). In recent years much effort has been made to improve prostate cancer (PCa) therapy. Novel drugs like Abiraterone or Enzalutamide, that target androgen receptor signaling to improve androgen deprivation therapy (ADT), or the chemotherapeutic drug docetaxel which is given after ADT-failure resulted in prolonged patient survival. However, the efficacy of these drugs is limited due to an inherent or acquired resistance during therapy. This limits treatment success and highlights the importance of identifying novel targets to improve PCa therapy. In this context the main aim of this study was to evaluate the expression and the functional significance of PIAS1 and BIRC5 protein expression in PCa cells and tumor tissue of PCa patients. Moreover, specific PIAS1 and BIRC5 knockdown experiments should clarify if targeting of these proteins can be used as a novel treatment approach for an improved PCa therapy. Screenings of PCa cells and PCa patients revealed elevated PIAS1 and BIRC5 protein expression. Moreover, specific PIAS1 and BIRC5 knockdown resulted in declined tumor growth and elevated apoptosis. The remaining PCa cells exhibited a reduced migratory, invasive, and colony forming capacity. Furthermore, PIAS1 significantly correlates with AR expression in PCa tissue and cell lines. Importantly, high PIAS1 levels predict shorter relapse free survival. The patient data are complemented by mechanistic and functional in vitro experiments which identify PIAS1 as an androgen responsive gene and a crucial factor for AR signaling via prevention of AR degradation. Strikingly, Abiraterone or Enzalutamide treatment in combination with PIAS1 depletion is even more effective than single drug treatment in multiple PCa cell models. In conclusion, the gained results for PIAS1 and BIRC5 are very promising and therefore, follow-up clinical studies and the development of specific PIAS1 inhibitors should be started.