Article,
Gbetagamma signaling promotes breast cancer cell migration and invasion
J Pharmacol Exp Ther, (January 2010)
DOI: 10.1124/jpet.109.164814
Abstract
Signaling through G-protein coupled receptors (GPCRs) promotes breast cancer metastasis. G proteins convey GPCR signals by dissociating into Galpha and Gbetagamma subunits. The aim of the present study was to determine whether blockade of Gbetagamma signaling suppresses breast cancer cell migration and invasion, critical components of metastasis. Conditioned media (CM) of NIH-3T3 fibroblasts is widely used as chemoattractants in in vitro cancer metastasis studies. Expression of a Gbetagamma scavenger peptide attenuated NIH-3T3 CM-induced migration and invasion of both metastatic breast cancer MDA-MB-231 and MDA-MB-436 cells by 40-50% without effects on cell viability. Migration and invasion of cells in response to NIH-3T3 CM were also blocked by M119K, a Gbetagamma inhibitor, with maximum inhibition exceeding 80% and IC(50) values of 1-2 microM. M119K also attenuated Rac-dependent formation of lamellipodia, a key structure required for metastasis. Constitutively active Rac1 rescued Gbetagamma blockade-mediated inhibition of breast cancer cell migration whereas dominant negative Rac1 inhibited cell migration similar to Gbetagamma blockade. Furthermore, M119K suppressed G(i)-protein coupled CXC chemokine receptor 4 (CXCR4)-dependent MDA-MB-231 cell migration by 80% with an IC(50) value of 1 microM, whereas tyrosine kinase receptor-dependent cell migration was significantly less inhibited. However, CXCR4-dependent inhibition of adenylyl cyclase, a G(i)alpha-mediated response in MDA-MB-231 cells, was not blocked by M119K but was blocked by pertussis toxin, which selectively inactivates G(i)alpha. This report is the first to directly demonstrate the role of Gbetagamma in cancer cell migration and invasion, and suggests that targeting Gbetagamma signaling pathways may provide a novel strategy for suppressing breast cancer metastasis.
