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

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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.

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Acknowledgements

This research was supported by National Institutes of Health Grant 5-PO1CA 77664, titled ‘High Throughput Genetic Analysis of Bladder Cancer’.

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  1. A Chatterjee and X Chang: These authors contributed equally to this work.

Authors and Affiliations

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

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

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  1. A Chatterjee
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  2. X Chang
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  3. J K Nagpal
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Chatterjee, A., Chang, X., Nagpal, J. et al. Targeting human 8-oxoguanine DNA glycosylase to mitochondria protects cells from 2-methoxyestradiol-induced-mitochondria-dependent apoptosis. Oncogene 27, 3710–3720 (2008). https://doi.org/10.1038/onc.2008.3

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