Activation of GRP/GRP-R signaling contributes to castrationresistant prostate cancer progression

Jingbo Qiao, Magdalena M. Grabowska, Ingrid S. Forestier-Roman, Janni Mirosevich, Thomas C. Case, Dai H. Chung, Justin M.M. Cates, Robert J. Matusik, H. Charles Manning, Renjie Jin

Research output: Contribution to journalArticle

6 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)61955-61969
Number of pages15
JournalOncotarget
Volume7
Issue number38
DOIs
StatePublished - Jan 1 2016
Externally publishedYes

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Keywords

  • Androgen receptor variants
  • GRP/GRP-R
  • NF-kappa B
  • Progression
  • Prostate cancer

ASJC Scopus subject areas

  • Oncology

Cite this

Qiao, J., Grabowska, M. M., Forestier-Roman, I. S., Mirosevich, J., Case, T. C., Chung, D. H., Cates, J. M. M., Matusik, R. J., Manning, H. C., & Jin, R. (2016). Activation of GRP/GRP-R signaling contributes to castrationresistant prostate cancer progression. Oncotarget, 7(38), 61955-61969. https://doi.org/10.18632/oncotarget.11326