Prostatic neuroendocrine cells (NE) are an integral part of prostate cancer (PCa) and are associated with PCa progression. As the current androgen deprivation therapy with anti-androgens may promote the neuroendocrine PCa (NEPCa) development, and few therapies can effectively suppress NEPCa, understanding the impact of NEPCa on PCa progression may help us to develop better therapies to battle PCa. Here, we found NEPCa cells could increase the docetaxel resistance of their neighboring PCa cells. Mechanism dissection revealed that through secretion of PTHrP, NEPCa cells could alter the p38/MAPK/Hsp27 signals in their neighboring PCa cells that resulted in increased androgen receptor (AR) activity via promoting AR nuclear translocation. The consequences of increased AR function might then increase docetaxel resistance via increasing p21 expression. In vivo xenograft mice experiments also confirmed that NEPCa could increase the docetaxel resistance of neighboring PCa, and targeting this newly identified PTHrP/p38/Hsp27/AR/p21 signaling pathway with either p38 inhibitor (SB203580) or shPTHrP may result in improving/restoring the docetaxel sensitivity to better suppress PCa.Oncogene advance online publication, 4 July 2016; doi:10.1038/onc.2016.135.
Oncogene. 2016 Jul 04 [Epub ahead of print]
Y Cui, Y Sun, S Hu, J Luo, L Li, X Li, S Yeh, J Jin, C Chang
Department of Urology, Peking University/First Hospital, Beijing, China., George Whipple Lab for Cancer Research, Departments of Pathology, Urology and Radiation Oncology and The Wilmot Cancer Center, University of Rochester Medical Center, Rochester, NY, USA., Department of Urology, Peking University/First Hospital, Beijing, China., George Whipple Lab for Cancer Research, Departments of Pathology, Urology and Radiation Oncology and The Wilmot Cancer Center, University of Rochester Medical Center, Rochester, NY, USA., George Whipple Lab for Cancer Research, Departments of Pathology, Urology and Radiation Oncology and The Wilmot Cancer Center, University of Rochester Medical Center, Rochester, NY, USA., Department of Urology, Peking University/First Hospital, Beijing, China., George Whipple Lab for Cancer Research, Departments of Pathology, Urology and Radiation Oncology and The Wilmot Cancer Center, University of Rochester Medical Center, Rochester, NY, USA., Department of Urology, Peking University/First Hospital, Beijing, China., George Whipple Lab for Cancer Research, Departments of Pathology, Urology and Radiation Oncology and The Wilmot Cancer Center, University of Rochester Medical Center, Rochester, NY, USA.