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Essential role of p53 in phenethyl isothiocyanate-induced apoptosis
Abstract:
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.
Insights
Phenethyl isothiocyanate (PEITC) effectively prevents cancer by inducing apoptosis, a programmed cell death process. This cancer chemopreventive activity relies on the p53 tumor suppressor pathway.
Area of Science:
- Oncology
- Molecular Biology
- Biochemistry
Background:
- Phenethyl isothiocyanate (PEITC) is a natural compound recognized for its potent cancer chemopreventive properties.
- Its efficacy is linked to modulating carcinogen metabolism and inducing apoptosis.
- Previous research suggests PEITC's role in cancer prevention, but the precise molecular mechanisms require further elucidation.
Purpose of the Study:
- To investigate the role of PEITC in inhibiting tumor promoter-induced cell transformation.
- To determine the specific molecular pathways involved in PEITC-induced apoptosis.
- To establish the dependency of PEITC's apoptotic effect on the p53 pathway.
Main Methods:
- Utilizing mouse epidermal JB6 cells to assess PEITC's effect on cell transformation induced by 12-O-tetradecanoylphorbol-13-acetate or epidermal growth factor.
- Analyzing PEITC-induced apoptosis and its correlation with cell transformation inhibition.
- Evaluating p53 protein expression and p53-dependent transactivation in response to PEITC.
- Comparing PEITC-induced apoptosis in p53 wild-type (p53 +/+) and p53 knockout (p53 -/-) cells.
- Assessing PEITC's apoptotic effect in cells with normal or deficient sphingomyelinase activity.
Main Results:
- PEITC effectively blocked tumor promoter-induced cell transformation in JB6 cells, with this inhibition correlating with apoptosis induction.
- PEITC treatment led to increased p53 protein expression and enhanced p53-dependent transactivation.
- Apoptosis was induced by PEITC in p53 +/+ cells but not in p53 -/- cells, confirming p53 dependency.
- PEITC induced apoptosis irrespective of the sphingomyelinase activity status of the cells.
- This study provides the first evidence that p53 elevation is a prerequisite for PEITC-induced apoptosis.
Conclusions:
- PEITC's cancer chemopreventive activity is significantly mediated by its ability to induce apoptosis through a p53-dependent mechanism.
- The findings highlight the critical role of the p53 pathway in PEITC's anti-cancer effects.
- This research elucidates a key molecular mechanism underlying PEITC's potential as a chemopreventive agent.