¹Head and Neck Cancer Research Division, Department of Otolaryngology-Head and Neck Surgery, The Johns Hopkins University, School of Medicine, Baltimore, MD, USA

Correspondence: Professor D Sidransky, Head and Neck Cancer Research Division, Department of Otolaryngology-Head and Neck Surgery, 1550 Orleans Street, Johns Hopkins University School of Medicine, Cancer Research Building II, Baltimore, MD 21231, USA. E-mail: dsidrans@jhmi.edu

²These authors contributed equally to this work.

Received 10 September 2007; Revised 30 November 2007; Accepted 21 December 2007; Published online 4 February 2008.

Abstract

2-Methoxyestradiol (2-ME), an endogenous estrogen metabolite of 17-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.