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, David Sidransky

Research output: Contribution to journalArticle

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

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Mitochondria
Apoptosis
Poly(ADP-ribose) Polymerases
HeLa Cells
BH3 Interacting Domain Death Agonist Protein
Cerulenin
G2 Phase Cell Cycle Checkpoints
Caspase 9
Mitochondrial Membrane Potential
Mitochondrial Membranes
Caspases
Caspase 3
human oxoguanine glycosylase 1
2-methoxyestradiol
Estradiol
Estrogens

Keywords

  • 2-methoxyestradiol
  • Fas activation
  • hOGG1
  • Mitochondria

ASJC Scopus subject areas

  • Molecular Biology
  • Cancer Research
  • Genetics

Cite this

Targeting human 8-oxoguanine DNA glycosylase to mitochondria protects cells from 2-methoxyestradiol-induced-mitochondria-dependent apoptosis. / Chatterjee, A.; Chang, X.; Nagpal, J. K.; Chang, S.; Upadhyay, S.; Califano, J.; Trink, B.; Sidransky, David.

In: Oncogene, Vol. 27, No. 26, 12.06.2008, p. 3710-3720.

Research output: Contribution to journalArticle

Chatterjee, A. ; Chang, X. ; Nagpal, J. K. ; Chang, S. ; Upadhyay, S. ; Califano, J. ; Trink, B. ; Sidransky, David. / Targeting human 8-oxoguanine DNA glycosylase to mitochondria protects cells from 2-methoxyestradiol-induced-mitochondria-dependent apoptosis. In: Oncogene. 2008 ; Vol. 27, No. 26. pp. 3710-3720.
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AB - 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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