INCREASED MANGANESE SUPEROXIDE-DISMUTASE ACTIVITY, PROTEIN, AND MESSENGER-RNA LEVELS AND CONCURRENT INDUCTION OF TUMOR-NECROSIS-FACTOR-ALPHA IN RADIATION-INITIATED SYRIAN-HAMSTER CELLS

The levels of the antioxidant enzyme manganese superoxide dismutase (M n-SOD) are frequently decreased in tumor cells and increased in normal cells upon treatment with ionizing radiation. We studied Mn-SOD at di fferent stages during the neoplastic conversion of radiation-initiated Syrian hamster embryo HDR-3 cells. Mn-SOD activity and the concentrat ion of Mn-SOD protein and mRNA increased gradually during the malignan t transformation of HDR-3 cells after radiation exposure; fully neopla stic cells showed greater Mn-SOD levels than preneoplastic and normal 84-3 cells. Inhibitors of superoxide (50) anion production (thenoyltri fluoroacetone and rotenone) decreased the concentration of Mn-SOD mRNA , raising the possibility that the generation of 50 radicals participa ted in the upregulation of Mn-SOD in cells transformed by exposure to radiation. We observed an increase in the concentration of tumor necro sis factor alpha (TNF alpha) in HDR-3 cells relative to mock-irradiate d cells. Together with the observation that TNF alpha stimulates the p roduction of SO by mitochondria and increases the level of Mn-SOD mRNA in other experimental systems, our results suggest that as normal 84- 3 cells undergo malignant transformation induced by ionizing radiation they produce TNF alpha to which the cells respond by increasing the c oncentration of Mn-SOD mRNA and protein and the activity of the enzyme . (C) 1996 Wiley-Liss, Inc.