title: Neuroendocrine prostate cancer (NEPCa) increased the neighboring PCa chemoresistance via altering the PTHrP/p38/Hsp27/androgen receptor (AR)/p21 signals.
abstract: 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.
authors.affiliation: 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.
authors.forename: Y
authors.initials: Y
authors.lastname: Cui
authors.affiliation: 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.
authors.forename: Y
authors.initials: Y
authors.lastname: Sun
authors.affiliation: 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.
authors.forename: S
authors.initials: S
authors.lastname: Hu
authors.affiliation: 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.
authors.forename: J
authors.initials: J
authors.lastname: Luo
authors.affiliation: 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.
authors.forename: L
authors.initials: L
authors.lastname: Li
authors.affiliation: Department of Urology, Peking University/First Hospital, Beijing, China.
authors.forename: X
authors.initials: X
authors.lastname: Li
authors.affiliation: 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.
authors.forename: S
authors.initials: S
authors.lastname: Yeh
authors.affiliation: Department of Urology, Peking University/First Hospital, Beijing, China.
authors.forename: J
authors.initials: J
authors.lastname: Jin
authors.affiliation: 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.|Sex Hormone Research Center, China Medical University/Hospital, Taichung, Taiwan.
authors.forename: C
authors.initials: C
authors.lastname: Chang
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D018278:Carcinoma, Neuroendocrine / Q000188:drug therapy / Q000378:metabolism*; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D000077143:Docetaxel; D019008:Drug Resistance, Neoplasm; D055551:HSP27 Heat-Shock Proteins / Q000378:metabolism*; D006801:Humans; D008297:Male; D011471:Prostatic Neoplasms / Q000188:drug therapy / Q000378:metabolism*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D044168:Receptor, Parathyroid Hormone, Type 1 / Q000378:metabolism*; D011944:Receptors, Androgen / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D043823:Taxoids / Q000494:pharmacology; D023041:Xenograft Model Antitumor Assays; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*
chemical_list: D000970:Antineoplastic Agents; D055551:HSP27 Heat-Shock Proteins; D047428:Protein Kinase Inhibitors; D044168:Receptor, Parathyroid Hormone, Type 1; D011944:Receptors, Androgen; D043823:Taxoids; D000077143:Docetaxel; D048051:p38 Mitogen-Activated Protein Kinases