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Essential Role of p53 in Phenethyl Isothiocyanate-induced Apoptosis¹

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

Phenethyl isothiocyanate (PEITC) is a natural product that is among the most effective cancer chemopreventive agents known. Mechanistic studies indicate that the chemopreventive activity of PEITC is associated with its favorable modification of carcinogen metabolism and its induction of apoptosis. Here, we found that PEITC blocks tumor promoter (12-O-tetradecanoylphorbol-13-acetate or epidermal growth factor)-induced cell transformation in mouse epidermal JB6 cells, and this inhibitory activity on cell transformation is correlated with induction of apoptosis. Most importantly, apoptosis induction by PEITC occurs through a p53-dependent pathway. This was demonstrated not only by results that PEITC induction of p53 protein expression and p53-dependent transactivation but also by PEITC-induced apoptosis in p53 +/+ cells but not in p53 -/- cells. In contrast, PEITC induced apoptosis in cells with both normal or deficient sphingomyelinase activity. Our results demonstrate for the first time that p53 elevation is required for PEITC-induced apoptosis, which may be involved in its cancer chemopreventive activity.

¹ This research was supported by The Hormel Foundation, National Cancer Institute Grants CA74916 and CA46535, and a Grant-in-Aid from the Graduate School of the University of Minnesota.

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: zgdong@smig.net.

Received 6/ 5/98. Accepted 7/30/98.

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