Resistance of Mitochondrial DNA-depleted Cells against Cell Death

Abstract

We have shown that mitochondrial DNA-depleted (ρ 0) SK-Hep1 hepatoma cells are resistant to apoptosis, contrary to previous papers reporting normal apoptotic susceptibility of ρ 0 cells. We studied the changes of gene expression in SK-Hep1 ρ 0 cells. DNA chip analysis showed that MnSOD expression was profoundly increased in ρ 0 cells. O 2 · ¯ contents increased during ρ 0 cell derivation but became normalized after establishment of ρ 0 phenotypes, suggesting that MnSOD induction is an adaptive process to increased O 2 · ¯ . ρ 0 cells were resistant to menadione, paraquat, or doxorubicin, and O 2 · ¯ contents after treatment with them were lower in ρ 0 cells compared with parental cells because of MnSOD overexpression. Expression levels and activity of glutathione peroxidases were also increased in ρ 0 cells, rendering them resistant to exogenous H 2 O 2. ρ 0 cells were resistant to p53, and intracellular ROS contents after p53 expression were lower compared with parental cells. Other types of ρ 0 cells also showed increased MnSOD expression and resistance against ROS. Heme oxygenase-1 expression was increased in ρ 0 cells, and a heme oxygenase-1 inhibitor decreased the induction of MnSOD in ρ 0 cells and their resistance against ROS donors. These results indicate that ρ 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.