Deregulation of catalase, not MnSOD, is associated with necrotic death of p53-defective DF-1 cells under antimycin A-induced oxidative stress.
One of distinct genetic alterations in spontaneously immortalized DF-1 cells was found to be dysfunction of p53 and E2F-1 as well as altered antioxidant gene expression (upregulation of MnSOD and downregulation of catalase). We have characterized the cellular responses of primary and immortal DF-1 cells to oxidative stress and found that DF-1 cells were more sensitive to oxidative stress than their primary counterparts when treated with antimycin A. The increased DF-1 cell death by oxidative stress was accompanied by an increase in the levels of intracellular superoxide anions and hydrogen peroxide. The cell death in DF-1 cells by antimycin A showed none of the hallmarks of apoptosis, but displayed a significantly increased necrotic cell population. Anti-apoptotic Bcl-2 failed to inhibit oxidative-induced necrotic cell death in the DF-1 cells. However, this necrotic cell death was significantly decreased by treatment with hydrogen peroxide scavengers such as sodium pyruvate and N-acetyl-cysteine. Interestingly, overexpression of human catalase in DF-1 cells endowed cells resistant to the oxidative stress by antimycin A treatment, although the downregulation of MnSOD by an antisense strategy showed no evident change in the cytotoxic effect caused by antimycin A. Taken together, the present study might provide new therapeutic approach for tumor cells having the loss of p53 function and the altered antioxidant functions.
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