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

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 expos...

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Bibliographic Details
Published in:Oncogene Vol. 27; no. 26; pp. 3710 - 3720
Main Authors: Chatterjee, A, Chang, X, Nagpal, J K, Chang, S, Upadhyay, S, Califano, J, Trink, B, Sidransky, D
Format: Journal Article
Language:English
Published: London Nature Publishing Group UK 12.06.2008
Nature Publishing
Nature Publishing Group
Subjects:
17β-Estradiol
8-Hydroxyguanine
Ageing, cell death
Apoptosis
Apoptosis - drug effects
Biological and medical sciences
Caspase-3
Caspases - physiology
Cell Biology
Cell cycle
Cell Cycle - drug effects
Cell physiology
Cell Survival - drug effects
Cell transformation and carcinogenesis. Action of oncogenes and antioncogenes
Cerulenin
Deoxyribonucleic acid
DNA
DNA Damage
DNA glycosylase
DNA Glycosylases - physiology
Estradiol
Estradiol - analogs & derivatives
Estradiol - pharmacology
Estrogens
Fundamental and applied biological sciences. Psychology
Genetics
HeLa Cells
Human Genetics
Humans
Hyperpolarization
Internal Medicine
Medicine
Medicine & Public Health
Membrane potential
Membrane Potential, Mitochondrial - drug effects
Mitochondria
Mitochondria - drug effects
Mitochondrial DNA
Molecular and cellular biology
Oncology
original-article
Physiological aspects
Poly(ADP-ribose)
Poly(ADP-ribose) polymerase
Poly(ADP-ribose) Polymerases - metabolism
Ribose
United States
activation
mitochondria
2-methoxyestradiol
Human
Targeting
Enzyme
Fas activation
Activation
Carcinogenesis
Glycosylases
Mitochondria
hOGG1
DNA
Hydrolases
Apoptosis
ISSN:0950-9232, 1476-5594, 1476-5594
Online Access:Get full text
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Summary: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 G 2 /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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ISSN:0950-9232
1476-5594
1476-5594
DOI:10.1038/onc.2008.3