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 17beta-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.
Chatterjee
A
A
Head and Neck Cancer Research Division, Department of Otolaryngology-Head and Neck Surgery, The Johns Hopkins University, School of Medicine, Baltimore, MD, USA.
Chang
X
X
Nagpal
J K
JK
Chang
S
S
Upadhyay
S
S
Califano
J
J
Trink
B
B
Sidransky
D
D
D000077584:2-Methoxyestradiol; D017209:Apoptosis / Q000187:drug effects*; D020169:Caspases / Q000502:physiology; D002453:Cell Cycle / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004249:DNA Damage; D045647:DNA Glycosylases / Q000502:physiology*; D004958:Estradiol / Q000031:analogs & derivatives* / Q000494:pharmacology; D006367:HeLa Cells; D006801:Humans; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D008928:Mitochondria / Q000187:drug effects*; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism
D004958:Estradiol; D000077584:2-Methoxyestradiol; D011065:Poly(ADP-ribose) Polymerases; D045647:DNA Glycosylases; C479058:oxoguanine glycosylase 1, human; D020169:Caspases