Catalase-overexpressing thymocytes are resistant to glucocorticoid-inducedapoptosis and exhibit increased net tumor growth

Glucocorticoids are used for the treatment of lymphoid neoplasms, taking ad vantage of the well-known ability of these compounds to cause apoptosis in lymphoid tissues, Previously, we have shown that dexamethasone, a synthetic glucocorticoid, causes a down-regulation of several antioxidant defense en zymes and proteins, including catalase and thioredoxin, concomitant with th e induction of apoptosis in WEHI7.2 mouse thymoma cells, To test whether th is down-regulation plays a critical role in the mechanism of steroid-induce d apoptosis, WEHI7.2 cells were transfected with rat catalase, Two clones, expressing 1.4-fold and 2.0-fold higher catalase specific activity, respect ively, when compared with vector-only transfectants were selected for furth er study, An increase to 1.4-fold parental cell catalase activity delayed c ell loss after dexamethasone treatment, whereas a 2.0-fold parental catalas e activity prevented dexamethasone-induced cell loss for 48 h after treatme nt. Dexamethasone treatment of the WEHI7.2 cells stimulated a release of cy tochrome c into the cytosol, Catalase-overexpressing cells showed a delay o r lack of cytochrome c release from the mitochondria, which correlated temp orally with the delay or prevention of cell loss in the culture after dexam ethasone treatment. A decreased amount of cell death from WEHI7.2 cells ove rexpressing catalase was also seen in tumor xenografts in severe combined i mmunodeficient mice when compared with tumors from vector-only transfected cells. Similarly, thioredoxin-overexpressing WEHI7.2 cells, shown previousl y to be apoptosis resistant, showed decreased cell death in tumor xenograft s, This resulted in larger tumors from cells overexpressing these proteins. Cell death in control transfectant tumor xenografts was primarily attribut able to apoptosis. In contrast, the cell death me observed in tumors from t hioredoxin- or catalase-overexpressing cells had a higher frequency of a no napoptotic, nonnecrotic type of cell death termed para-apoptosis. These dat a suggest that: (a) oxidative stress plays a critical role in steroid-induc ed apoptosis prior to the commitment of the cells to undergo apoptosis; and (b) resistance to oxidative stress can contribute to tumor growth.