Resistance of mitochondrial DNA-depleted cells against cell death: role of mitochondrial superoxide dismutase.
We have shown that mitochondrial DNA-depleted (rho(0)) SK-Hep1 hepatoma cells are resistant to apoptosis, contrary to previous papers reporting normal apoptotic susceptibility of rho(0) cells. We studied the changes of gene expression in SK-Hep1 rho(0) cells. DNA chip analysis showed that MnSOD expression was profoundly increased in rho(0) cells. O(2)(.) contents increased during rho(0) cell derivation but became normalized after establishment of rho(0) phenotypes, suggesting that MnSOD induction is an adaptive process to increased O(2)(.). rho(0) cells were resistant to menadione, paraquat, or doxorubicin, and O(2)(.) contents after treatment with them were lower in rho(0) cells compared with parental cells because of MnSOD overexpression. Expression levels and activity of glutathione peroxidases were also increased in rho(0) cells, rendering them resistant to exogenous H(2)O(2). rho(0) cells were resistant to p53, and intracellular ROS contents after p53 expression were lower compared with parental cells. Other types of rho(0) cells also showed increased MnSOD expression and resistance against ROS. Heme oxygenase-1 expression was increased in rho(0) cells, and a heme oxygenase-1 inhibitor decreased the induction of MnSOD in rho(0) cells and their resistance against ROS donors. These results indicate that rho(0) cells are resistant to cell death contrary to previous reports and suggest that an adaptive increase in the expression of antioxidant enzymes renders cancer cells or aged cells with frequent mitochondrial DNA mutations to resist against oxidative stress, host anti-cancer surveillance, or chemotherapeutic agents, conferring survival advantage on them.
Park
Sun Young
SY
Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, 50 Irwondong Kangnam-ku, Seoul 135-710, Korea.
Chang
Inik
I
Kim
Ja-Young
JY
Kang
Sang Won
SW
Park
Se-Ho
SH
Singh
Keshav
K
Lee
Myung-Shik
MS
D000818:Animals; D017209:Apoptosis; D015153:Blotting, Western; D006528:Carcinoma, Hepatocellular; D004272:DNA, Mitochondrial / Q000032:analysis* / Q000502:physiology*; D004317:Doxorubicin / Q000494:pharmacology; D004351:Drug Resistance; D015870:Gene Expression; D005979:Glutathione Peroxidase / Q000235:genetics; D006861:Hydrogen Peroxide / Q000378:metabolism / Q000494:pharmacology; D007340:Insulinoma; D008113:Liver Neoplasms; D051379:Mice; D018384:Oxidative Stress; D010190:Pancreatic Neoplasms; D010269:Paraquat / Q000494:pharmacology; D017382:Reactive Oxygen Species / Q000032:analysis / Q000494:pharmacology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013482:Superoxide Dismutase / Q000235:genetics; D013481:Superoxides / Q000032:analysis / Q000378:metabolism; D014407:Tumor Cells, Cultured; D024483:Vitamin K 3 / Q000494:pharmacology
D004272:DNA, Mitochondrial; D017382:Reactive Oxygen Species; D013481:Superoxides; D024483:Vitamin K 3; D004317:Doxorubicin; D006861:Hydrogen Peroxide; D005979:Glutathione Peroxidase; D013482:Superoxide Dismutase; D010269:Paraquat