PI-3 kinase in signal transduction, cell transformation, and as a target for chemoprevention of cancer.

Abstract

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.

• Authors: Z Dong, C Huang, W Y Ma
• Journal: Anticancer research (Anticancer Res) 1999 Sep-Oct Vol. 19 Issue 5A Pg. 3743-7 ISSN: 0250-7005 [Print] Greece
• PMID: 10625951 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Review)

Chemical References

• Anticarcinogenic Agents
• Insulin
• Phosphoinositide-3 Kinase Inhibitors
• Transcription Factor AP-1
• Epidermal Growth Factor
• Phytic Acid
• Protein Kinase C
• Tetradecanoylphorbol Acetate

Topics

• Animals
• Anticarcinogenic Agents (pharmacology)
• Cell Transformation, Neoplastic (drug effects)
• Epidermal Growth Factor (pharmacology)
• Humans
• Insulin (pharmacology)
• Phosphatidylinositol 3-Kinases (physiology)
• Phosphoinositide-3 Kinase Inhibitors
• Phytic Acid (pharmacology)
• Protein Kinase C (physiology)
• Signal Transduction (drug effects)
• Tetradecanoylphorbol Acetate (pharmacology)
• Transcription Factor AP-1 (metabolism)