Abstract
Signaling through G‐protein coupled receptors (GPCRs) promotes breast cancer metastasis. G‐proteins convey GPCR signals by dissociating into Gα and Gβγ subunits. The aim of this study was to determine whether blockade of Gβγ suppresses breast cancer cell migration and invasion, critical steps of metastasis. Transwell chamber assays showed that expression of a Gβγ scavenger peptide derived from β‐adrenergic receptor kinase, attenuated migration and invasion of both breast cancer MDA‐MB‐231 and MDA‐MB‐436 cells by 50%. Migration and invasion of those cells were also blocked by M119K, an inhibitor of Gβγ, with maximum inhibition of 80% and IC50 of 1–2 μM. Activation of Gi‐protein coupled CXC chemokine receptor 4 (CXCR4) promotes breast cancer metastasis. M119K suppressed CXCR4‐dependent MDA‐MB‐231 cell migration by 75% with IC50 of 0.9 μM. Immunostaining analysis indicated that 10 μM M119K attenuated CXCR4‐stimulated, Rac‐dependent formation of lamellipodia, a key structure required for metastasis. In contrast, CXCR4‐dependent inhibition of adenylyl cyclase, a Giα‐mediated response, was not blocked by M119K but was blocked by pertussis toxin, which inactivates Giα. This is the first to directly demonstrate the role of Gβγ in breast cancer metastasis and suggests that targeting Gβγ signaling pathways may provide a novel strategy for suppressing breast cancer metastasis. Supported by Nebraska State LB595.
Published Version
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