Infiltrating bone marrow mesenchymal stem cells (BM-MSCs) increase prostate cancer cell invasion via altering the CCL5/HIF2a/androgen receptor signals

Abstract

Several infiltrating cells in the tumor microenvironment could influence the cancer progression via secreting various cytokines. Here, we found the CCL5 secreted from BM-MSCs suppressed androgen receptor (AR) signals via enhancing the expression of hypoxia inducible factor 2a (HIF2a) in prostate cancer (PCa) cells. Mechanism dissection revealed that the increased HIF2a might alter the AR-HSP90 interaction to suppress the AR transactivation, and inhibition of HIF2a reversed the BM-MSCs-increased PCa stem cell population and PCa cells invasion. Importantly, CCL5 could suppress the prolyl hydroxylases (PHDs) expression, which might then lead to suppress VHL-mediated HIF2a ubiquitination. Together, these results demonstrated that the CCL5 signals from infiltrating BM-MSC cells to HIF2a signals within PCa cells might play a key role to increase PCa stem cell population and PCa metastasis via altering the AR signals. Targeting this newly identified CCL5/HIF2a/AR axis signal axis may allow us to develop a novel way to suppress PCa metastasis.