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

Jingbo Qiao1,2, Magdalena M Grabowska1,3, Ingrid S Forestier-Roman4

  • 1Department of Cancer Biology, Vanderbilt University Medical Center, Nashville, TN, USA.

Oncotarget
|August 20, 2016
PubMed

Insights

Anti-androgen therapy can unexpectedly drive prostate cancer progression by increasing gastrin-releasing peptide (GRP) and its receptor (GRP-R), leading to castration-resistant prostate cancer (CRPC) via NF-κB activation and androgen receptor splice variants (ARVs).

Area of Science:

  • Oncology
  • Endocrinology
  • Molecular Biology

Background:

  • Androgen receptor splice variants (ARVs) are crucial in castration-resistant prostate cancer (CRPC) development and resistance to anti-androgen therapies.
  • NF-κB signaling activation increases ARVs expression, promoting CRPC progression, but its activation mechanism in CRPC remains unclear.

Purpose of the Study:

  • To elucidate the mechanism of NF-κB activation in CRPC.
  • To investigate the role of gastrin-releasing peptide (GRP) and its receptor (GRP-R) in CRPC progression.
  • To identify potential therapeutic targets for advanced CRPC.

Main Methods:

  • Investigated the effect of long-term anti-androgen treatment on GRP and GRP-R expression in prostate cancer (PC) cells.
  • Analyzed the role of GRP/GRP-R signaling in activating NF-κB and increasing ARVs expression.
  • Assessed the impact of AR-V7 knockdown on anti-androgen sensitivity in PC cells with overexpressed GRP/GRP-R signaling.

Main Results:

  • Long-term anti-androgen treatment increased GRP and GRP-R expression in PC cells.
  • Activation of GRP/GRP-R signaling promoted CRPC progression by activating NF-κB and increasing ARVs expression, notably AR-V7.
  • Knockdown of AR-V7 restored anti-androgen sensitivity in PC cells with overexpressed GRP/GRP-R signaling.

Conclusions:

  • Androgen-deprivation therapy (ADT) induces GRP/GRP-R activity, leading to NF-κB activation and increased AR-V7 expression, driving progression to CRPC.
  • Both prostate adenocarcinoma and small cell neuroendocrine prostate cancer express GRP-R.
  • Targeting GRP-R offers a novel therapeutic strategy for advanced CRPC.
Keywords:
GRP/GRP-RNF-kappa Bandrogen receptor variantsprogressionprostate cancer

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