G-protein αolf subunit promotes cellular invasion, survival, and neuroendocrine differentiation in digestive and urogenital epithelial cells

• Published in: Oncogene Vol. 21; no. 25; pp. 4020 - 4031
• Main Authors: REGNAULD, Karine, NGUYEN, Quang-Dé, VAKAET, Luc, BRUYNEEL, Erik, LAUNAY, Jean-Marie, ENDO, Takeshi, MAREEL, Marc, GESPACH, Christian, EMAMI, Shahin
• Format: Journal Article
• Language: English
• Published: Basingstoke Nature Publishing 06.06.2002; Nature Publishing Group
• Subjects: Apoptosis; Axonogenesis; Biological and medical sciences; Cancer; Cell physiology; Cell transformation and carcinogenesis. Action of oncogenes and antioncogenes; Collagen; Epithelial cells; Fundamental and applied biological sciences. Psychology; G proteins; Genetic aspects; Guanosine triphosphatase; Invasiveness; Kinases; Metastases; Molecular and cellular biology; Parathyroid; Parathyroid hormone; Parathyroid hormone-related protein; Phenotypes; Physiological aspects; Platelet-activating factor; Prostate; Prostate cancer; Protein kinase A; Protein kinase C; Proteinase-activated receptor 1; Proteins; RhoA protein; Risk factors; Solid tumors; Src protein; Starvation; Tumors; Wortmannin; France; Enzyme; Triphosphoric monoester hydrolases; src; Transferases; PKA; dGTPase; Esterases; Subunit; PTHrP; cAMP; Carcinogenesis; Survival; Rho GTPases; Kinase; trefoil factors; PI3'- Kinase; Hydrolases; Epithelial cell; Differentiation; Protein-tyrosine kinase; G protein
• ISSN: 0950-9232; 1476-5594
• DOI: 10.1038/sj.onc.1205498

The heterotrimeric G-protein subunits Gα and Gβγ are involved in cellular transformation and tumor development. Here, we report the expression of Gαolf in human digestive and urogenital epithelial cells using RT–PCR and Western blot. When the constitutively activated form of GαolfQ214L (AGαolf) was stably transfected in canine kidney MDCKts.src and human colonic HCT-8/S11 epithelial cells, it induced cellular invasion in collagen gels. AGαolf-mediated invasion was abrogated by agonists of platelet activating factor receptors (PAF-R) and protease-activated receptors -1 (PAR-1), pharmacological inhibitors of PI3′-Kinase (wortmannin), protein kinase C (Gö6976 and GF109203X), Rho GTPase (C3T exoenzyme), but was independent of protein kinase A. Accordingly, the invasive phenotype induced by AGαolf in HCT-8/S11 cells was reversed by the RhoA antagonist RhoD (G26V). Although AGαolf protected MDCKts.src cells against serum starvation-mediated apoptosis via a Rho-independent pathway, both AGαolf and Rho inhibition by C3T induced neuroendocrine-like differentiation linked to extensive neurite outgrowth and parathyroid hormone-related protein expression in human prostatic LNCaP-AGαolf cells. Since prostate tumors with a larger neuroendocrine cell population display increased invasiveness, persistent activation of the G-protein αolf may exert convergent adverse effects on cellular invasion and survival in solid tumors during the neoplastic progression towards metastasis.