Infiltrating bone marrow mesenchymal stem cells (BM-MSCs) increase prostate cancer cell invasion via altering the CCL5/HIF2α/androgen receptor signals.
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.
Department of Pathology, University of Rochester, Rochester, NY 14642, USA.|Department of Urology, University of Rochester, Rochester, NY 14642, USA.|Department of Radiation Oncology, University of Rochester, Rochester, NY 14642, USA.|Department of Biology, University of Rochester, Rochester, NY 14642, USA.|The Wilmot Cancer Center, University of Rochester, Rochester, NY 14642, USA.
Jie
J
Luo
Department of Pathology, University of Rochester, Rochester, NY 14642, USA.|Department of Urology, University of Rochester, Rochester, NY 14642, USA.|Department of Radiation Oncology, University of Rochester, Rochester, NY 14642, USA.|Department of Biology, University of Rochester, Rochester, NY 14642, USA.|The Wilmot Cancer Center, University of Rochester, Rochester, NY 14642, USA.
Soo Ok
SO
Lee
Department of Pathology, University of Rochester, Rochester, NY 14642, USA.|Department of Urology, University of Rochester, Rochester, NY 14642, USA.|Department of Radiation Oncology, University of Rochester, Rochester, NY 14642, USA.|Department of Biology, University of Rochester, Rochester, NY 14642, USA.|The Wilmot Cancer Center, University of Rochester, Rochester, NY 14642, USA.
Yun
Y
Cui
Department of Pathology, University of Rochester, Rochester, NY 14642, USA.|Department of Urology, University of Rochester, Rochester, NY 14642, USA.|Department of Radiation Oncology, University of Rochester, Rochester, NY 14642, USA.|Department of Biology, University of Rochester, Rochester, NY 14642, USA.|The Wilmot Cancer Center, University of Rochester, Rochester, NY 14642, USA.
Rachel
R
Yang
Department of Pathology, University of Rochester, Rochester, NY 14642, USA.|Department of Urology, University of Rochester, Rochester, NY 14642, USA.|Department of Radiation Oncology, University of Rochester, Rochester, NY 14642, USA.|Department of Biology, University of Rochester, Rochester, NY 14642, USA.|The Wilmot Cancer Center, University of Rochester, Rochester, NY 14642, USA.|Sex Hormone Research Center, Department of Urology, The First Affiliated Hospital, Xian Jiaotong University, Xian, 710061, China.
Lei
L
Li
Department of Pathology, University of Rochester, Rochester, NY 14642, USA.|Department of Urology, University of Rochester, Rochester, NY 14642, USA.|Department of Radiation Oncology, University of Rochester, Rochester, NY 14642, USA.|Department of Biology, University of Rochester, Rochester, NY 14642, USA.|The Wilmot Cancer Center, University of Rochester, Rochester, NY 14642, USA.|Sex Hormone Research Center, China Medical University and Hospital, Taichung, 404, Taiwan.
Chawnshang
C
Chang
D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000378:metabolism*; D001854:Bone Marrow Cells / Q000166:cytology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D018946:Chemokine CCL5 / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic; D018841:HSP90 Heat-Shock Proteins / Q000378:metabolism; D006801:Humans; D008297:Male; D059630:Mesenchymal Stem Cells / Q000166:cytology*; D051379:Mice; D008819:Mice, Nude; D009361:Neoplasm Invasiveness; D009362:Neoplasm Metastasis; D009368:Neoplasm Transplantation; D011471:Prostatic Neoplasms / Q000473:pathology*; D060888:Real-Time Polymerase Chain Reaction; D011944:Receptors, Androgen / Q000378:metabolism*; D054875:Ubiquitination; D000099162:Endothelial PAS Domain-Containing Protein 1
D051792:Basic Helix-Loop-Helix Proteins; D018946:Chemokine CCL5; D018841:HSP90 Heat-Shock Proteins; D011944:Receptors, Androgen; D000099162:Endothelial PAS Domain-Containing Protein 1; C410798:AR protein, human; C483024:CCL5 protein, human
CCL5; HIF2α; androgen receptor; bone marrow mesenchymal stem cells; prostate cancer