Inositol hexaphosphate inhibits cell transformation and activator protein 1 activation by targeting phosphatidylinositol-3' kinase.

Inositol hexaphosphate (InsP6) is the most abundant inositol phosphate found in plants. In mammalian cells, the concentrations of InsP6 are between 10 and 100 microM. Previous work has indicated that InsP6 is an effective cancer chemopreventive and chemotherapeutic agent. However, the molecular mechanisms involved in the inhibition of carcinogenesis by InsP6 remain unclear. In this study, we investigated the influence of InsP6 on tumor promoter-induced cell transformation and signal transduction pathways leading to activator protein 1 activation, which is considered to play a crucial role in tumor promotion. InsP6 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 InsP6 profoundly impairs epidermal growth factor- or phorbol ester-induced JB6 cell transformation and extracellular signal-regulated protein kinases activation, as well as activator protein 1 activation. These results provide the first evidence that the molecular mechanism of InsP6 antitumor promotion effect targets and blocks PI-3 kinase activation and demonstrate that PI-3 kinase can serve as a molecular target for the development of cancer chemopreventive agents.