EVIDENCE THAT CHANGES IN SE-GLUTATHIONE PEROXIDASE LEVELS AFFECT THE SENSITIVITY OF HUMAN TUMOR-CELL LINES TO N-3 FATTY-ACIDS

The human lung adenocarcinoma cell line A-427 is significantly more se nsitive to cytotoxic lipid peroxidation products of eicosapentaenoic a cid (EPA) and docosahexaenoic acid (DHA) than the human lung adenocarc inoma cell line SK-LU-1, and the glioblastoma cell lines A-172 and U-8 7 MG, The cytotoxic effect as well as lipid peroxidation were abolishe d by vitamin E, The differential sensitivities of the cell lines were not correlated to the levels of lipid peroxidation products (measured as the end product malondialdehyde), indicating differences in sensiti vities to products of lipid peroxidation, The high sensitivity of A-42 7 is apparently due to a low level of selenium-dependent glutathione p eroxidase (GSH-Px), because pretreatment with sodium selenite (250 nM) increased the GSH-Px activity 3- to 4-fold and protected the cells al most completely against the growth inhibitory effect of DHA, Furthermo re, 2-phenyl-1,2-benzisoselenazol-3 (2H)-one (ebselen) a seleno-organi c GSH-Px mimic, suppressed the cytotoxic action of DHA to A-427 in a d ose dependent manner, Northern analysis demonstrated that pretreatment with sodium selenite (250 nM) was accompanied by an increased level o f GSH-Px mRNA (1.8-fold) in A-427 cells, while the level remained unch anged under the same conditions in DHA/EPA-resistant A-172 cells, In a ddition, the level of selenophosphate synthetase mRNA (SelD), a key in termediate in tRNA(Sec) formation, increased 1.2- to 1.7-fold in A-427 and A-172 cells after pretreatment with sodium selenite, These result s indicate that upregulation of GSH-Px activity by sodium selenite in the EPA/DHA sensitive cell line A-427 may be due to an increase in mRN As for GSH-Px and a precursor important for formation of tRNA(Sec) whi ch is required for incorporation of selenocysteine in GSH-Px during tr anslation, These results demonstrate an important role for GSH-Px in t he cellular defence against cytotoxic lipid peroxidation products, Fur thermore, measurement of GSH-Px activities in tumour cells may be one useful biochemical predictor for their sensitivities to polyunsaturate d fatty acids.