Abstract
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.
Highlights
SK-Hep1 hepatoma cells are resistant to apoptosis, contrary to previous papers reporting normal apoptotic susceptibility of 0 cells
We observed that manganese superoxide dismutase (MnSOD) and other antioxidant enzymes such as glutathione peroxidases (GPx) are up-regulated in those cells leading to an efficient disposal of increased oxidative stress and increased resistance against ROS or p53, which might be related to the resistance of cancer cells [8, 9] or aged cells [10, 11] with mtDNA mutations against apoptosis and their avoidance of the host surveillance
Increased MnSOD Expression in SK-Hep1 0 Cells—First, we studied the changes of gene expression in SK-Hep1 0 cells using DNA chip analysis (Genomic Tree, Taejon, Korea)
Summary
Heme oxygenase-1 expression was increased in 0 cells, and a heme oxygenase-1 inhibitor decreased the induction of MnSOD in 0 cells and their resistance against ROS donors These results indicate that 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. We have reported that mtDNA-depleted hepatoma cells (SK-Hep1 0 cells) are resistant to TRAIL-induced apoptosis, which is consistent with the importance of mitochondria in cell death [7] It is not clearly elucidated how those cells with mitochondrial dysfunction resist cell death. Our results indicate that 0 cells are resistant to various forms of cell death contrary to previous reports and that intact mitochondrial function is crucial for the execution of cell death
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