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Inositol Hexaphosphate Inhibits Cell Transformation and Activator Protein 1 Activation by Targeting Phosphatidylinositol-3' Kinase¹

The Hormel Institute, University of Minnesota, Austin, Minnesota 55912 [C. H., W-Y. M., Z. D.], and University of Minnesota Cancer Center, Minneapolis, Minnesota 55455 [S. S. H.]

Inositol hexaphosphate (InsP₆) is the most abundant inositol phosphate found in plants. In mammalian cells, the concentrations of InsP₆ are between 10 and 100 µM. 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.

¹ This work was supported in part by the Hormel Foundation.

² To whom requests for reprints should be addressed, at The Hormel Institute, University of Minnesota, 801 16th Avenue NE, Austin, MN 55912. Phone: (507) 437-9640; Fax: (507) 437-9606; E-mail: zdong@wolf.co.net.

Received 4/28/97. Accepted 5/28/97.

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