Targeting human 8-oxoguanine DNA glycosylase (hOGG1) to mitochondria enhances cisplatin cytotoxicity in hepatoma cells

2.50
Hdl Handle:
http://hdl.handle.net/10541/70465
Title:
Targeting human 8-oxoguanine DNA glycosylase (hOGG1) to mitochondria enhances cisplatin cytotoxicity in hepatoma cells
Authors:
Zhang, Haihong; Mizumachi, 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
Abstract:
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.
Affiliation:
Department of Pathology, University of Arkansas for Medical Sciences, 4301 West Markham Street, Little Rock, AR 72205, USA.
Citation:
Targeting human 8-oxoguanine DNA glycosylase (hOGG1) to mitochondria enhances cisplatin cytotoxicity in hepatoma cells. 2007, 28 (8):1629-37 Carcinogenesis
Journal:
Carcinogenesis
Issue Date:
Aug-2007
URI:
http://hdl.handle.net/10541/70465
DOI:
10.1093/carcin/bgm072
PubMed ID:
17389610
Type:
Article
Language:
en
ISSN:
0143-3334
Appears in Collections:
All Paterson Institute for Cancer Research

Full metadata record

DC FieldValue Language
dc.contributor.authorZhang, Haihong-
dc.contributor.authorMizumachi, Takatsugu-
dc.contributor.authorCarcel-Trullols, Jaime-
dc.contributor.authorLi, Liwen-
dc.contributor.authorNaito, Akihiro-
dc.contributor.authorSpencer, Horace J-
dc.contributor.authorSpring, Paul M-
dc.contributor.authorSmoller, Bruce R-
dc.contributor.authorWatson, Amanda J-
dc.contributor.authorMargison, Geoffrey P-
dc.contributor.authorHiguchi, Masahiro-
dc.contributor.authorFan, Chun-Yang-
dc.date.accessioned2009-06-15T12:09:37Z-
dc.date.available2009-06-15T12:09:37Z-
dc.date.issued2007-08-
dc.identifier.citationTargeting human 8-oxoguanine DNA glycosylase (hOGG1) to mitochondria enhances cisplatin cytotoxicity in hepatoma cells. 2007, 28 (8):1629-37 Carcinogenesisen
dc.identifier.issn0143-3334-
dc.identifier.pmid17389610-
dc.identifier.doi10.1093/carcin/bgm072-
dc.identifier.urihttp://hdl.handle.net/10541/70465-
dc.description.abstractMany 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.en
dc.language.isoenen
dc.subjectCell Line Tumouren
dc.subjectLiver Canceren
dc.subject.meshAntineoplastic Agents-
dc.subject.meshCarcinoma, Hepatocellular-
dc.subject.meshCell Line, Tumor-
dc.subject.meshCisplatin-
dc.subject.meshDNA Damage-
dc.subject.meshDNA Glycosylases-
dc.subject.meshDNA Repair-
dc.subject.meshDNA, Mitochondrial-
dc.subject.meshDNA-(Apurinic or Apyrimidinic Site) Lyase-
dc.subject.meshHumans-
dc.subject.meshLiver Neoplasms-
dc.subject.meshMitochondria, Liver-
dc.subject.meshMitochondrial Proteins-
dc.subject.meshN-Glycosyl Hydrolases-
dc.subject.meshProtein Transport-
dc.subject.meshRNA, Messenger-
dc.subject.meshTransgenes-
dc.titleTargeting human 8-oxoguanine DNA glycosylase (hOGG1) to mitochondria enhances cisplatin cytotoxicity in hepatoma cellsen
dc.typeArticleen
dc.contributor.departmentDepartment of Pathology, University of Arkansas for Medical Sciences, 4301 West Markham Street, Little Rock, AR 72205, USA.en
dc.identifier.journalCarcinogenesisen
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