Neuroendocrine prostate cancer (NEPCa) increased the neighboring PCa chemoresistance via altering the PTHrP/p38/Hsp27/androgen receptor (AR)/p21 signals

作者：Cui, Y.; Sun, Y.; Hu, S.; Luo, J.; Li, L.; Li, X.; Yeh, S.; Jin, J.^*; Chang, C.^*

来源：Oncogene, 2016, 35(47): 6065-6076.

DOI：10.1038/onc.2016.135

• SHOCK-PROTEIN 27
• ACQUIRED DOCETAXEL RESISTANCE
• MITOXANTRONE PLUS PREDNISONE
• ANDROGEN RECEPTOR
• P38 MAPK
• CELL-SURVIVAL
• GROWTH
• EXPRESSION
• ACTIVATION
• KINASE

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.

• 出版日期2016-11-24
• 单位中国医科大学; 北京大学