Lower induction of p53 and decreased apoptosis in NQO1-null mice lead to increased sensitivity to chemical-induced skin carcinogenesis

Karim Iskander, Amos Gaikwad, Marilene Paquet, Delwin J. Long, Cory Brayton, Roberto Barrios, Anil K. Jaiswal

Research output: Contribution to journalArticle

71 Scopus citations

Abstract

NAD(F)H:quinone oxidoreductase 1 (NQO1) is a cytosolic protein that catalyzes metabolic detoxification of quinones and protects cells against redox cycling and oxidative stress. NQO1-null mice deficient in NQO1 protein showed increased sensitivity to 7,12-dimethylbenz(a)anthracene- and benzo(a)pyrene-induced skin carcinogenesis. In the present studies, we show that benzo(a)pyrene metabolite benzo(a)pyrene-trans-7,8-dihydrodiol-9,10-epoxide and not benzo(a)pyrene quinones contributed to increased benzo(a) pyrene-induced skin tumors in NQO1-null mice. An analysis of untreated skin revealed an altered intracellular redox state due to accumulation of NADH and reduced levels of NAD/NADH in NQO1-null mice as compared with wild-type mice. Treatment with benzo(a)pyrene failed to significantly increase p53 and apoptosis in the skin of NQO1-null mice when compared with wild-type mice. These results led to the conclusion thai altered intracellular redox state along with lack of induction of p53 and decreased apoptosis plays a significant role in increased sensitivity of NQO1-null mice to benzo(a) pyrene-induced skin cancer.

Original languageEnglish (US)
Pages (from-to)2054-2058
Number of pages5
JournalCancer research
Volume65
Issue number6
DOIs
StatePublished - Mar 15 2005

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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