ESSENTIAL ROLE OF P53 IN PHENETHYL ISOTHIOCYANATE-INDUCED APOPTOSIS

Phenethyl isothiocyanate (PEITC) is a natural product that is among th e most effective cancer chemopreventive agents known. Mechanistic stud ies indicate that the chemopreventive activity of PEITC is associated with its favorable modification of carcinogen metabolism and its induc tion of apoptosis. Here, we found that PEITC blocks tumor promoter (12 -O-tetradecanoyIphorbol-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 apopt osis. Most importantly, apoptosis induction by PEITC occurs through a p53 -/- dependent pathway. This was demonstrated not only by results t hat PEITC induction of p53 protein expression and p53-dependent transa ctivation 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 demons trate for the first time that p53 elevation is required for PEITC-indu ced apoptosis, which may be involved in its cancer chemopreventive act ivity.