Requirement for G proteins in insulin-like growth factor-I-induced growth of prostate cells.
Elevated levels of IGF-I in the circulation are associated with increased risk for the development of prostate cancer in men, and transgenic expression of human IGF-I in mouse epithelial prostate cells results in spontaneous prostate tumorigenesis. Little, however, is known about the mechanisms involved in the IGF-I-regulated growth of prostate cells. Here, we have demonstrated that treatment with IGF-I induces the activation of the mitogenic extracellular signal-regulated kinase (ERK) pathway and the growth of human prostate cells. Stimulation with IGF-I also promoted the tyrosine phosphorylation of epidermal growth factor receptor (EGFR). Signal relay from IGF-I to ERK requires heterotrimeric G proteins and EGFR; inhibition of Gi/o protein activation by pertussis toxin, or EGFR by tyrphostin AG1478 obliterated the ability of IGF-I to promote ERK activation. Further, treatment with pertussis toxin inhibited the IGF-I-mediated prostate cell growth. These data demonstrated the requirement of heterotrimeric G proteins in IGF-I-regulated prostate cell growth and suggest the potential utility of the G proteins as effective drug targets to combat this common cancer.
Department of Surgery, Duke University Medical Center, Durham, North Carolina 27710, USA.
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Lyons-Darden
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Daaka
D015153:Blotting, Western; D002455:Cell Division / Q000187:drug effects*; D002461:Cell Line, Transformed; D019204:GTP-Binding Proteins / Q000502:physiology*; D006801:Humans; D047468:Immunoprecipitation; D007334:Insulin-Like Growth Factor I / Q000494:pharmacology*; D008297:Male; D010766:Phosphorylation; D011467:Prostate / Q000166:cytology*
D007334:Insulin-Like Growth Factor I; D019204:GTP-Binding Proteins