PI-3 kinase in signal transduction, cell transformation, and as a target for chemoprevention of cancer.
Phosphatidylinositol-3 kinase (PI-3 K) plays a central role in a broad range of biological effects. However, little is known about its role in phorbol ester- or epidermal growth factor (EGF)-induced signal transduction to the transcriptional machinery of the nucleus and in tumor promoter-induced cell transformation. We have used JB6 cells to study the role of PI-3 K in 12-O-tetradecanoylphorbol-13-acetate (TPA)- or EGF-induced AP-1 activation and neoplastic cell transformation. We demonstrated that TPA, EGF and insulin induce PI-3 K activity in JB6 cells. The induced PI-3 K activity was blocked by a dominant negative mutant of PI-3 K, and by wortmannin or LY294002. Blocking of PI-3 K activity by these inhibitors also blocked TPA- or EGF-induced AP-1 activity and cell transformation. Furthermore, we have investigated the role of PKC and its isozymes in the synergistic induction of PI-3 K by TPA and insulin and found that bisindolylmaleimide, a PKC inhibitor, inhibits TPA-induced PI-3 K. Overexpression of a dominant negative PKC epsilon, but not dominant negative PKC alpha, blocks the TPA- or TPA plus insulin-induced PI-3 K activity. Inositol hexaphosphate (InsP6) is one of the most promising chemopreventive agents as demonstrated by Shamsuddin et al. and others. InsP6 profoundly inhibits EGF- or TPA-induced cell transformation and the signal transduction cascade to Erks and AP-1 activation. InsP6 also inhibits TPA- or EGF-induced PI-3 K activity in vivo and in vitro. These results suggest that the anticarcinogenesis action of InsP6 may be through inhibition of PI-3 K and inhibition of the AP-1 pathway. Because InsP6 is a naturally occurring compound with virtually no toxicity, and may be an effective anticarcinogenesis agent in humans, PI-3 K and AP-1 activities may be useful biomarkers for the effectiveness of InsP6 in clinical studies.
Dong
Z
Z
Hormel Institute, University of Minnesota, Austin 55912, USA. zgdong@smig.net
Huang
C
C
Ma
W Y
WY
D000818:Animals; D016588:Anticarcinogenic Agents / Q000494:pharmacology*; D002471:Cell Transformation, Neoplastic / Q000187:drug effects*; D004815:Epidermal Growth Factor / Q000494:pharmacology; D006801:Humans; D007328:Insulin / Q000494:pharmacology; D019869:Phosphatidylinositol 3-Kinases / Q000502:physiology*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010833:Phytic Acid / Q000494:pharmacology; D011493:Protein Kinase C / Q000502:physiology; D015398:Signal Transduction / Q000187:drug effects*; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D018808:Transcription Factor AP-1 / Q000378:metabolism
D016588:Anticarcinogenic Agents; D004815:Epidermal Growth Factor; D007328:Insulin; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010833:Phytic Acid; D011493:Protein Kinase C; D013755:Tetradecanoylphorbol Acetate; D018808:Transcription Factor AP-1