INOSITOL HEXAPHOSPHATE INHIBITS CELL-TRANSFORMATION AND ACTIVATOR PROTEIN-1 ACTIVATION BY TARGETING PHOSPHATIDYLINOSITOL-3' KINASE

Inositol hexaphosphate (InsP(6)) is the most abundant inositol phospha te found in plants. In mammalian cells, the concentrations of InsP(6) are between 10 and 100 mu M. Previous work has indicated that InsP(6) is an effective cancer chemopreventive and chemotherapeutic agent. How ever, the molecular mechanisms involved in the inhibition of carcinoge nesis by InsP(6) remain unclear. In this study, we investigated the in fluence of InsP(6) on tumor promoter-induced cell transformation and s ignal transduction pathways leading to activator protein 1 activation, which is considered to play a crucial role in tumor promotion. InsP(6 ) markedly blocks epidermal growth factor-induced phosphatidylinositol -3 (PI-3) kinase activity in a dose-dependent manner in JB6 cells and directly in vitro. Blocking PI-3 kinase activity by InsP(6) profoundly impairs epidermal growth factor- or phorbol ester-induced JB6 cell tr ansformation and extracellular signal-regulated protein kinases activa tion, as well as activator protein 1 activation. These results provide the first evidence that the molecular mechanism of InsP(6) antitumor promotion effect targets and blocks PI-3 kinase activation and demonst rate that PI-3 kinase can serve as a molecular target for the developm ent of cancer chemopreventive agents.