Gβγ signaling promotes breast cancer cell migration and invasion

Joseph K. Kirui, Yan Xie, Dennis W. Wolff, Haihong Jiang, Peter W. Abel, Yaping Tu

Research output: Contribution to journalArticle

44 Citations (Scopus)

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 the present study was to determine whether blockade of Gβγ signaling suppresses breast cancer cell migration and invasion, which are critical components of metastasis. Conditioned media (CM) of NIH-3T3 fibroblasts are widely used as chemoattractants in in vitro cancer metastasis studies. Expression of a Gβγ 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 to 50% without effects on cell viability. Migration and invasion of cells in response to NIH-3T3 CM were also blocked by 8-(4,5,6-trihydroxy-3-oxo-3H-xanthen-9-yl)-1-naph-thalene- carboxylic acid) (M119K), a Gβγ inhibitor, with maximum inhibition exceeding 80% and half-maximal inhibitory concentration (IC50) values of 1 to 2 μM. M119K also attenuated Rac-dependent formation of lamellipodia, a key structure required for metastasis. Constitutively active Rac1 rescued Gβγ blockade-mediated inhibition of breast cancer cell migration, whereas dominant negative Rac1 inhibited cell migration similar to Gβγ blockade. Furthermore, M119K suppressed Gi protein-coupled CXC chemokine receptor 4 (CXCR4)-dependent MDA-MB-231 cell migration by 80% with an IC50 value of 1 μM, whereas tyrosine kinase receptor-dependent cell migration was significantly less inhibited. However, CXCR4-dependent inhibition of adenylyl cyclase, a Giα- mediated response in MDA-MB-231 cells, was not blocked by M119K but was blocked by pertussis toxin, which selectively inactivates Giα. This report is the first to directly demonstrate the role of Gβγ in cancer cell migration and invasion and suggests that targeting Gβγ signaling pathways may provide a novel strategy for suppressing breast cancer metastasis.

Original languageEnglish
Pages (from-to)393-403
Number of pages11
JournalJournal of Pharmacology and Experimental Therapeutics
Volume333
Issue number2
DOIs
StatePublished - May 2010

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Cell Movement
Breast Neoplasms
Neoplasm Metastasis
Conditioned Culture Medium
CXCR4 Receptors
G-Protein-Coupled Receptors
Inhibitory Concentration 50
Pseudopodia
Chemotactic Factors
Pertussis Toxin
Receptor Protein-Tyrosine Kinases
Carboxylic Acids
GTP-Binding Proteins
Adenylyl Cyclases
Neoplasms
Cell Survival
Fibroblasts
Peptides
Proteins

All Science Journal Classification (ASJC) codes

  • Pharmacology
  • Molecular Medicine
  • Medicine(all)

Cite this

Gβγ signaling promotes breast cancer cell migration and invasion. / Kirui, Joseph K.; Xie, Yan; Wolff, Dennis W.; Jiang, Haihong; Abel, Peter W.; Tu, Yaping.

In: Journal of Pharmacology and Experimental Therapeutics, Vol. 333, No. 2, 05.2010, p. 393-403.

Research output: Contribution to journalArticle

Kirui, Joseph K. ; Xie, Yan ; Wolff, Dennis W. ; Jiang, Haihong ; Abel, Peter W. ; Tu, Yaping. / Gβγ signaling promotes breast cancer cell migration and invasion. In: Journal of Pharmacology and Experimental Therapeutics. 2010 ; Vol. 333, No. 2. pp. 393-403.
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