H. Manning
Faculty Member
Last active: 3/22/2018

Activation of GRP/GRP-R signaling contributes to castration-resistant prostate cancer progression.

Qiao J, Grabowska MM, Forestier-Roman IS, Mirosevich J, Case TC, Chung DH, Cates JM, Matusik RJ, Manning HC, Jin R
Oncotarget. 2016 7 (38): 61955-61969

PMID: 27542219 · PMCID: PMC5308703 · DOI:10.18632/oncotarget.11326

Numerous studies indicate that androgen receptor splice variants (ARVs) play a critical role in the development of castration-resistant prostate cancer (CRPC), including the resistance to the new generation of inhibitors of androgen receptor (AR) action. Previously, we demonstrated that activation of NF-κB signaling increases ARVs expression in prostate cancer (PC) cells, thereby promoting progression to CRPC. However, it is unclear how NF-κB signaling is activated in CRPC. In this study, we report that long-term treatment with anti-androgens increases a neuroendocrine (NE) hormone - gastrin-releasing peptide (GRP) and its receptor (GRP-R) expression in PC cells. In addition, activation of GRP/GRP-R signaling increases ARVs expression through activating NF-κB signaling. This results in an androgen-dependent tumor progressing to a castrate resistant tumor. The knock-down of AR-V7 restores sensitivity to antiandrogens of PC cells over-expressing the GRP/GRP-R signaling pathway. These findings strongly indicate that the axis of Androgen-Deprivation Therapy (ADT) induces GRP/GRP-R activity, activation NF-κB and increased levels of AR-V7 expression resulting in progression to CRPC. Both prostate adenocarcinoma and small cell NE prostate cancer express GRP-R. Since the GRP-R is clinically targetable by analogue-based approach, this provides a novel therapeutic approach to treat advanced CRPC.

MeSH Terms (17)

Adenocarcinoma Androgen Antagonists Androgens Antineoplastic Agents Cell Line, Tumor Disease Progression Gastrin-Releasing Peptide Gene Expression Regulation, Neoplastic Genetic Variation Humans Male Prostatic Neoplasms, Castration-Resistant Receptors, Androgen Receptors, Bombesin RNA Splicing Signal Transduction Transcription, Genetic

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