Abstract 161: Adult myogenic stem cells inhibit prostate cancer cell proliferation and increase docetaxel-mediated cell toxicity

Abstract

Abstract Current treatments for prostate cancer (PCa) are primarily based on use of anti-androgen agents to prevent disease progression and bone lesions. However, metastatic PCa (mPCa) continues to progress in an androgen-independent manner, and consequently, bone and muscle tissues deteriorate, often resulting in severe pain and fragility. Adult stem cells have been used in regenerative medicine approaches for many years for treating human diseases through gene therapy. We have demonstrated for nearly two decades that a population of slow-adhering myogenic progenitor cells, called muscle progenitor cells (MPCs), has tremendous ability to regenerate bone, skeletal muscle, cartilage, nerve, and cardiac muscle after injury. However, to date, the potential therapeutic use of MPCs in cancers has not yet been investigated. We hypothesized that MPCs can inhibit proliferation and survival of PCa cells and increase docetaxel-induced cytotoxicity of the PCa cells. Moreover, MPCs may be effective in decreasing PCa-induced skeletal lesions and promote bone and muscle tissue repair. The objective of this study was to evaluate the paracrine roles of secreted factors from MPCs with respect to proliferation and survival of PCa cells. Here we showed that co-culture of PC3 and C42B cells with MPCs in transwell inserts strongly decreased PCa cell proliferation and survival by activating CDK inhibitors (p16 and p27) and apoptotic BBC3 and NOXA genes. Analysis of factors secreted by MPCs using ELISA protein array and mass spectrometry identified several proteins with known antiproliferative functions, including IGFBP6/7, pigment epithelium-derived factor, HPCAL1, NO, and SPARC. Additionally, conditioned media (CM) from MPCs increased the docetaxel-induced cytotoxicity of both androgen-dependent and -independent PCa cells. Molecular analysis also showed decreased expression of AR, MLL, FOXA1, TWF1, and TGIF1, which are known oncogenic regulators of PCa progression. Since metastatic PCa causes both osteolytic and osteoblastic lesions through the secretion of RANKL and BMPs, respectively, we then showed that treatment of PCa cells with OPG and noggin, antagonists of RANKL and BMPs, respectively, inhibited their cell proliferation. Further, CM from PCa cells pretreated with noggin and OPG resulted in decreased osteoblast activity in primary osteoblasts and decreased osteoclast activity in macrophage cells, respectively, when compared to CM from untreated PCa cells. These results suggest that noggin and OPG could be used as therapeutic proteins for reducing PCa-induced skeletal lesions through MPC gene delivery. Taken together, our data suggest that use of adult stem cell-based therapy along with current chemotherapy agents (e.g., docetaxel) is a promising effective strategy for treatment of PCa and preventing metastatic skeletal lesions. Citation Format: Krishna M. Sinha, Rozita Yarmand, Reid Andrew, Johnny Huard. Adult myogenic stem cells inhibit prostate cancer cell proliferation and increase docetaxel-mediated cell toxicity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 161.