Reactivation of mutant p53 by a dietary-related compound phenethyl isothiocyanate inhibits tumor growth

M. Aggarwal, R. Saxena, E. Sinclair, Y. Fu, A. Jacobs, M. Dyba, X. Wang, I. Cruz, D. Berry, B. Kallakury, S. C. Mueller, S. D. Agostino, G. Blandino, M. L. Avantaggiati, F. L. Chung

Research output: Contribution to journalArticlepeer-review

Abstract

Mutations in the p53 tumor-suppressor gene are prevalent in human cancers. The majority of p53 mutations are missense, which can be classified into contact mutations (that directly disrupts the DNA-binding activity of p53) and structural mutations (that disrupts the conformation of p53). Both of the mutations can disable the normal wild-type (WT) p53 activities. Nevertheless, it has been amply documented that small molecules can rescue activity from mutant p53 by restoring WT tumor-suppressive functions. These compounds hold promise for cancer therapy and have now entered clinical trials. In this study, we show that cruciferous-vegetable-derived phenethyl isothiocyanate (PEITC) can reactivate p53 mutant under in vitro and in vivo conditions, revealing a new mechanism of action for a dietary-related compound. PEITC exhibits growth-inhibitory activity in cells expressing p53 mutants with preferential activity toward p53R175, one of the most frequent ‘hotspot’ mutations within the p53 sequence. Mechanistic studies revealed that PEITC induces apoptosis in a p53R175 mutant-dependent manner by restoring p53 WT conformation and transactivation functions. Accordingly, in PEITC-treated cells the reactivated p53R175 mutant induces apoptosis by activating canonical WT p53 targets, inducing a delay in S and G2/M phase, and by phosphorylating ATM/CHK2. Interestingly, the growth-inhibitory effects of PEITC depend on the redox state of the cell. Further, PEITC treatments render the p53R175 mutant sensitive to degradation by the proteasome and autophagy in a concentration-dependent manner. PEITC-induced reactivation of p53R175 and its subsequent sensitivity to the degradation pathways likely contribute to its anticancer activities. We further show that dietary supplementation of PEITC is able to reactivate WT activity in vivo as well, inhibiting tumor growth in xenograft mouse model. These findings provide the first example of mutant p53 reactivation by a dietary compound and have important implications for cancer prevention and therapy.Cell Death and Differentiation advance online publication, 3 June 2016; doi:10.1038/cdd.2016.48.

Original languageEnglish
JournalCell Death and Differentiation
DOIs
Publication statusAccepted/In press - Jun 3 2016

ASJC Scopus subject areas

  • Cell Biology
  • Molecular Biology

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