Infiltrating bone marrow mesenchymal stem cells (BM-MSCs) increase prostate cancer cell invasion via altering the CCL5/HIF2α/androgen receptor signals
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Jie Luo1,2,3,4,5, Soo Ok Lee1,2,3,4,5, Yun Cui1,2,3,4,5, Rachel Yang1,2,3,4,5, Lei Li1,2,3,4,5,6, Chawnshang Chang1,2,3,4,5,7
1Department of Pathology, University of Rochester, Rochester, NY 14642, USA
2Department of Urology, University of Rochester, Rochester, NY 14642, USA
3Department of Radiation Oncology, University of Rochester, Rochester, NY 14642, USA
4Department of Biology, University of Rochester, Rochester, NY 14642, USA
5The Wilmot Cancer Center, University of Rochester, Rochester, NY 14642, USA
6Sex Hormone Research Center, Department of Urology, The First Affiliated Hospital, Xian Jiaotong University, Xian 710061, China
7Sex Hormone Research Center, China Medical University and Hospital, Taichung, 404, Taiwan
Chawnshang Chang, e-mail: [email protected]
Lei Li, e-mail: [email protected]
Keywords: CCL5, bone marrow mesenchymal stem cells, HIF2α, androgen receptor, prostate cancer
Received: February 26, 2015 Accepted: July 17, 2015 Published: July 27, 2015
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 2α (HIF2α) in prostate cancer (PCa) cells. Mechanism dissection revealed that the increased HIF2α might alter the AR-HSP90 interaction to suppress the AR transactivation, and inhibition of HIF2α 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 HIF2α ubiquitination. Together, these results demonstrated that the CCL5 signals from infiltrating BM-MSC cells to HIF2α 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/HIF2α/AR axis signal axis may allow us to develop a novel way to suppress PCa metastasis.
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