GPRC6A regulates prostate cancer progression

Prostate. 2012 Mar;72(4):399-409. doi: 10.1002/pros.21442. Epub 2011 Jun 16.


Background: GPRC6A is a nutrient sensing GPCR that is activated in vitro by a variety of ligands, including amino acids, calcium, zinc, osteocalcin (OC), and testosterone. The association between nutritional factors and risk of prostate cancer, the finding of increased expression of OC in prostate cancer cells, and the association between GPRC6A and risk of prostate cancer in Japanese men implicates a role of GPRC6A in prostate cancer.

Methods: We examined if GPRC6A is expressed in human prostate cancer cell lines and used siRNA-mediated knockdown GPRC6A expression in prostate cancer cells to explore the function of GPRC6A in vitro. To assess the role of GPRC6A in prostate cancer progression in vivo, we intercrossed Gprc6a(-/-) mice onto the TRAMP mouse prostate cancer model.

Results: GPRC6A transcripts were markedly increased in prostate cancer cell lines 22Rv1, PC-3, and LNCaP, compared to the normal prostate RWPE-1 cell line. In addition, a panel of GPRC6A ligands, including calcium, OC, and arginine, exhibited in prostate cancer cell lines a dose-dependent stimulation of ERK activity, cell proliferation, chemotaxis, and prostate specific antigen and Runx2 gene expression. These responses were inhibited by siRNA-mediated knockdown of GPRC6A. Finally, transfer of Gprc6a deficiency onto a TRAMP mouse model of prostate cancer significantly retarded prostate cancer progression and improved survival of compound Gprc6a(-/-) /TRAMP mice.

Conclusions: GPRC6A is a novel molecular target for regulating prostate growth and cancer progression. Increments in GPRC6A may augment the ability of prostate cancer cells to proliferate in response to dietary and bone derived ligands.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Adenocarcinoma / metabolism*
  • Adenocarcinoma / pathology*
  • Animals
  • Arginine / pharmacology
  • Calcium / pharmacology
  • Cell Line, Tumor
  • Cell Proliferation* / drug effects
  • Chemotaxis / drug effects
  • Core Binding Factor Alpha 1 Subunit / metabolism
  • Disease Models, Animal
  • Disease Progression*
  • Humans
  • In Vitro Techniques
  • Male
  • Mice
  • Mice, Knockout
  • Osteocalcin / pharmacology
  • Prostate / metabolism
  • Prostate / pathology
  • Prostate-Specific Antigen / metabolism
  • Prostatic Neoplasms / metabolism*
  • Prostatic Neoplasms / pathology*
  • RNA, Messenger / metabolism
  • RNA, Small Interfering / pharmacology
  • Receptors, G-Protein-Coupled / deficiency
  • Receptors, G-Protein-Coupled / genetics
  • Receptors, G-Protein-Coupled / metabolism*


  • Core Binding Factor Alpha 1 Subunit
  • GPRC6A protein, human
  • RNA, Messenger
  • RNA, Small Interfering
  • RUNX2 protein, human
  • Receptors, G-Protein-Coupled
  • Osteocalcin
  • Arginine
  • Prostate-Specific Antigen
  • Calcium