4.7 Article

Novel role of Giα2 in cell migration: Downstream of PI3-kinase-AKT and Rac1 in prostate cancer cells

Journal

JOURNAL OF CELLULAR PHYSIOLOGY
Volume 234, Issue 1, Pages 802-815

Publisher

WILEY
DOI: 10.1002/jcp.26894

Keywords

epidermal growth factor; F-actin; G-protein coupled receptors; lamellipodia; migration

Funding

  1. National Institutes of Health [G12MD007590, P20MD002285]
  2. Georgia Research Alliance

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Tumor cell motility is the essential step in cancer metastasis. Previously, we showed that oxytocin and epidermal growth factor (EGF) effects on cell migration in prostate cancer cells require Gi alpha 2 protein. In the current study, we investigated the interactions among G-protein coupled receptor (GPCR), Gi alpha 2, PI3-kinase, and Rac1 activation in the induction of migratory and invasive behavior by diverse stimuli. Knockdown and knockout of endogenous Gi alpha 2 in PC3 cells resulted in attenuation of transforming growth factor beta 1 (TGF beta 1), oxytocin, SDF-1 alpha, and EGF effects on cell migration and invasion. In addition, knockdown of Gi alpha 2 in E006AA cells attenuated cell migration and overexpression of Gi alpha 2 in LNCaP cells caused significant increase in basal and EGF-stimulated cell migration. Pretreatment of PC3 cells with Pertussis toxin resulted in attenuation of TGF beta 1- and oxytocin-induced migratory behavior and PI3-kinase activation without affecting EGF-induced PI3-kinase activation and cell migration. Basal- and EGF-induced activation of Rac1 in PC3 and DU145 cells were not affected in cells after Gi alpha 2 knockdown. On the other hand, Gi alpha 2 knockdown abolished the migratory capability of PC3 cells overexpressing constitutively active Rac1. The knockdown or knockout of Gi alpha 2 resulted in impaired formation of lamellipodia at the leading edge of the migrating cells. We conclude that Gi alpha 2 protein acts at two different levels which are both dependent and independent of GPCR signaling to induce cell migration and invasion in prostate cancer cells and its action is downstream of PI3-kinase-AKT-Rac1 axis.

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