Targeting human 8-oxoguanine DNA glycosylase to mitochondria protects cells from 2-methoxyestradiol-induced-mitochondria-dependent apoptosis

A. Chatterjee, X. Chang, J. K. Nagpal, S. Chang, S. Upadhyay, J. Califano, B. Trink, D. Sidransky

Research output: Contribution to journalArticlepeer-review

Abstract

2-Methoxyestradiol (2-ME), an endogenous estrogen metabolite of 17β-estradiol, is known to induce mitochondria-mediated apoptosis through several mechanisms. We sought to study the effect of mitochondrialy targeted hOGG1 (MTS-hOGG1) on HeLa cells exposed to 2-ME. MTS-hOGG1-expressing cells exposed to 2-ME showed increased cellular survival and had significantly less G2/M cell cycle arrest compared to vector-only-transfected cells. In addition, 2-ME exposure resulted in an increase in mitochondrial membrane potential, increased apoptosis, accompanied by higher activation of caspase-3, -9, cleavage of Bid to tBid and protein poly(ADP-ribose) polymerase (PARP) cleavage in HeLa cells lacking MTS-hOGG1. Fas inhibitors cerulenin or C75 inhibited 2-ME-induced caspase activation, PARP cleavage, apoptosis and reversed mitochondrial membrane hyperpolarization, thereby recapitulating the increased expression of MTS-hOGG1. Hence, MTS-hOGG1 plays an important protective role against 2-ME-mediated mitochondrial damage by blocking apoptosis induced through the Fas pathway.

Original languageEnglish (US)
Pages (from-to)3710-3720
Number of pages11
JournalOncogene
Volume27
Issue number26
DOIs
StatePublished - Jun 12 2008

Keywords

  • 2-methoxyestradiol
  • Fas activation
  • Mitochondria
  • hOGG1

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Cancer Research

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