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) that are associated with PCa progression. As the current androgen-deprivation therapy (ADT) 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 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 sh-PTHrP may result in improving/restoring the docetaxel sensitivity to better suppress PCa.

Targeting MCT4 to reduce lactic acid secretion and glycolysis for treatment of neuroendocrine prostate cancer

“…Further investigations into how these changes facilitate NEPC development could be a promising area of research, especially given its contribution to metastasis and the hypoxic response . It has also been suggested that in prostatic tumors containing a mixture of NE and adenocarcinoma cells, certain paracrine factors secreted by NE cells could facilitate the growth and aggressiveness of neighboring adenocarcinoma cells . Whether the increased secretion of lactic acid from NE cells could function in an analogous paracrine fashion to enhance PCa aggressiveness would be an intriguing area for further study.…”

“…13,14 It has also been suggested that in prostatic tumors containing a mixture of NE and adenocarcinoma cells, certain paracrine factors secreted by NE cells could facilitate the growth and aggressiveness of neighboring adenocarcinoma cells. 15,16 Whether the increased secretion of lactic acid from NE cells could function in an analogous paracrine fashion to enhance PCa aggressiveness would be an intriguing area for further study. Finally, inhibition of glucose metabolism via CD44 has also been reported to sensitize NEPC cells to platinum-based chemotherapy.…”

Molecular model for neuroendocrine prostate cancer progression

“…Although the functions of these NE peptides remain to be fully elucidated, some factors such as bombesin, neurotensin, serotonin, calcitonin and thyroid‐stimulating hormone may have potential mitogenic effects . In addition, the conditional medium of NEPC cells could promote chemoresistance in surrounding AdPC cells by modulating the PTHrP/p38/Hsp27/AR/p21 axis . Concurrently, benign and tumour‐associated NE cells were reported to have increased expressions of survival factors including survivin and Bcl‐2 .…”

The previously uncharacterized lncRNA APP promotes prostate cancer progression by acting as a competing endogenous RNA

“…Previous studies have reported that miR218 served as a tumor suppressor in high-grade localized PCa and in metastatic cells, 18 and that miR218 could target CDH2 and ZEB2, thereby preventing EMT in lung cancer. 29,30 We performed MS2-RIP and Ago2-RIP to confirm that lncAPP binds miR218 directly, and by overexpressing/downregulating lncAPP expression levels to conduct Ago2-RIP, we observed declining/increasing enrichment of ZEB2 and CDH2 mRNA to the Ago2-based RISC, which might suggest that lncAPP could compete with ZEB2 and CDH2 transcripts for binding miR218. We analyzed the mRNA expression levels of lncAPP, CDH2 and ZEB2 in RNA-seq data, and conducted immunohistochemistry of CDH2/ZEB2 and in situ hybridization of lncAPP in PCa tissues.…”