Targeting human 8-oxoguanine DNA glycosylase (hOGG1) to mitochondria enhances cisplatin cytotoxicity in hepatoma cells
Authors
Zhang, HaihongMizumachi, Takatsugu
Carcel-Trullols, Jaime
Li, Liwen
Naito, Akihiro
Spencer, Horace J
Spring, Paul M
Smoller, Bruce R
Watson, Amanda J
Margison, Geoffrey P
Higuchi, Masahiro
Fan, Chun-Yang
Affiliation
Department of Pathology, University of Arkansas for Medical Sciences, 4301 West Markham Street, Little Rock, AR 72205, USA.Issue Date
2007-08
Metadata
Show full item recordAbstract
Many chemoradiation therapies cause DNA damage through oxidative stress. An important cellular mechanism that protects cells against oxidative stress involves DNA repair. One of the primary DNA repair mechanisms for oxidative DNA damage is base excision repair (BER). BER involves the tightly coordinated function of four enzymes (glycosylase, apurinic/apyrimidinic endonuclease, polymerase and ligase), in which 8-oxoguanine DNA glycosylase 1 initiates the cycle. An imbalance in the production of any one of these enzymes may result in the generation of more DNA damage and increased cell killing. In this study, we targeted mitochondrial DNA to enhance cancer chemotherapy by over-expressing a human 8-oxoguanine DNA glycosylase 1 (hOGG1) gene in the mitochondria of human hepatoma cells. Increased hOGG1 transgene expression was achieved at RNA, protein and enzyme activity levels. In parallel, we observed enhanced mitochondrial DNA damage, increased mitochondrial respiration rate, increased membrane potential and elevated free radical production. A greater proportion of the hOGG1-over-expressing hepatoma cells experienced apoptosis. Following exposure to a commonly used chemotherapeutic agent, cisplatin, cancer cells over-expressing hOGG1 displayed much shortened long-term survival when compared with control cells. Our results suggest that over-expression of hOGG1 in mitochondria may promote mitochondrial DNA damage by creating an imbalance in the BER pathway and sensitize cancer cells to cisplatin. These findings support further evaluation of hOGG1 over-expression strategies for cancer therapy.Citation
Targeting human 8-oxoguanine DNA glycosylase (hOGG1) to mitochondria enhances cisplatin cytotoxicity in hepatoma cells. 2007, 28 (8):1629-37 CarcinogenesisJournal
CarcinogenesisDOI
10.1093/carcin/bgm072PubMed ID
17389610Type
ArticleLanguage
enISSN
0143-3334ae974a485f413a2113503eed53cd6c53
10.1093/carcin/bgm072
Scopus Count
Collections
Related articles
- Different organization of base excision repair of uracil in DNA in nuclei and mitochondria and selective upregulation of mitochondrial uracil-DNA glycosylase after oxidative stress.
- Authors: Akbari M, Otterlei M, Peña-Diaz J, Krokan HE
- Issue date: 2007 Apr 14
- Expression of human oxoguanine glycosylase 1 or formamidopyrimidine glycosylase in human embryonic kidney 293 cells exacerbates methylmercury toxicity in vitro.
- Authors: Ondovcik SL, Preston TJ, McCallum GP, Wells PG
- Issue date: 2013 Aug 15
- TAp63gamma regulates hOGG1 and repair of oxidative damage in cancer cell lines.
- Authors: Upadhyay S, Chatterjee A, Trink B, Sommer M, Ratovitski E, Sidransky D
- Issue date: 2007 May 18
- Imbalancing the DNA base excision repair pathway in the mitochondria; targeting and overexpressing N-methylpurine DNA glycosylase in mitochondria leads to enhanced cell killing.
- Authors: Fishel ML, Seo YR, Smith ML, Kelley MR
- Issue date: 2003 Feb 1
- Repair of 8-oxodeoxyguanosine lesions in mitochondrial dna depends on the oxoguanine dna glycosylase (OGG1) gene and 8-oxoguanine accumulates in the mitochondrial dna of OGG1-defective mice.
- Authors: de Souza-Pinto NC, Eide L, Hogue BA, Thybo T, Stevnsner T, Seeberg E, Klungland A, Bohr VA
- Issue date: 2001 Jul 15