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Inhibition of tumor cell migration and metastasis by the proton-sensing GPR4 receptor

Reid D Castellone1, Nancy R Leffler, Lixue Dong

  • 1Department of Internal Medicine, Brody School of Medicine, East Carolina University, Greenville, NC, United States.

Cancer Letters
|September 16, 2011
PubMed

Insights

Proton-sensing G protein-coupled receptor 4 (GPR4) activation by acidic tumor environments inhibits cancer cell migration and invasion. This finding suggests GPR4 as a potential therapeutic target for reducing tumor metastasis.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cell Biology

Background:

  • The tumor microenvironment's acidic pH can influence cancer progression.
  • G protein-coupled receptor 4 (GPR4) is a pH-sensing receptor implicated in cellular responses.
  • Understanding GPR4's role in cancer is crucial for developing new therapies.

Purpose of the Study:

  • To investigate the effect of GPR4 activation by acidic pH on tumor cell behavior.
  • To elucidate the molecular mechanisms underlying GPR4-mediated inhibition of cancer cell motility.
  • To evaluate the in vivo impact of GPR4 on melanoma metastasis.

Main Methods:

  • Overexpression of GPR4 in B16F10 melanoma and TRAMP-C1 prostate cancer cells.
  • In vitro assays: cell migration, Matrigel invasion, and transendothelial invasion.
  • Molecular analysis: RhoA activation and actin stress fiber formation.
  • In vivo studies: intravenous injection of B16F10 cells in mice to assess pulmonary metastasis.
  • Pharmacological manipulation using a Rho activator (CN01).

Main Results:

  • GPR4 overexpression and acidic pH significantly inhibited B16F10 and TRAMP-C1 cell migration and invasion.
  • Acidosis-induced GPR4 stimulation activated RhoA and promoted actin stress fiber formation.
  • In vivo, GPR4 overexpression reduced pulmonary metastasis of B16F10 melanoma by approximately 80%.
  • Treatment with a Rho activator mimicked the inhibitory effects of GPR4 activation on cell motility and metastasis.

Conclusions:

  • GPR4 activation by acidic tumor microenvironments suppresses tumor cell migration and invasion.
  • The Rho GTPase pathway plays a significant role in mediating GPR4's anti-motility effects.
  • GPR4 represents a potential therapeutic target for inhibiting cancer cell metastasis.

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