Targeting human 8-oxoguanine DNA glycosylase (hOGG1) to mitochondria enhances cisplatin cytotoxicity in hepatoma cells.
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.
Zhang
Haihong
H
Department of Pathology, University of Arkansas for Medical Sciences, 4301 West Markham Street, Little Rock, AR 72205, USA.
Mizumachi
Takatsugu
T
Carcel-Trullols
Jaime
J
Li
Liwen
L
Naito
Akihiro
A
Spencer
Horace J
HJ
Spring
Paul M
PM
Smoller
Bruce R
BR
Watson
Amanda J
AJ
Margison
Geoffrey P
GP
Higuchi
Masahiro
M
Fan
Chun-Yang
CY
D000970:Antineoplastic Agents / Q000633:toxicity*; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy* / Q000201:enzymology*; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000633:toxicity*; D004249:DNA Damage / Q000502:physiology; D045647:DNA Glycosylases; D004260:DNA Repair / Q000502:physiology; D004272:DNA, Mitochondrial / Q000378:metabolism; D043603:DNA-(Apurinic or Apyrimidinic Site) Lyase / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008113:Liver Neoplasms / Q000188:drug therapy* / Q000201:enzymology*; D008930:Mitochondria, Liver / Q000201:enzymology* / Q000235:genetics; D024101:Mitochondrial Proteins / Q000235:genetics / Q000378:metabolism*; D009699:N-Glycosyl Hydrolases / Q000235:genetics / Q000378:metabolism*; D021381:Protein Transport / Q000235:genetics; D012333:RNA, Messenger / Q000378:metabolism; D019076:Transgenes
D000970:Antineoplastic Agents; D004272:DNA, Mitochondrial; D024101:Mitochondrial Proteins; D012333:RNA, Messenger; D045647:DNA Glycosylases; D009699:N-Glycosyl Hydrolases; C479058:oxoguanine glycosylase 1, human; D043603:DNA-(Apurinic or Apyrimidinic Site) Lyase; D002945:Cisplatin