DOXORUBICIN-INDUCED ALTERATIONS OF C-MYC AND C-JUN GENE-EXPRESSION INRAT GLIOBLASTOMA CELLS - ROLE OF C-JUN IN DRUG-RESISTANCE AND CELL-DEATH

We studied the effect of doxorubicin on the expression of c-myc and c- jun in the rat glioblastoma cell line C6 and its doxorubicin-resistant variant C6 0.5, at equitoxic exposures. For quantitation, the mRNA le vels of these oncogenes were related to those of two domestic genes, b eta-actin and glyceraldehyde phosphate dehydrogenase. After a transien t overexpression of the genes during the first hour of incubation, the re was a selective, dose-dependent down regulation of both genes by do xorubicin in the sensitive cells. In the resistant cell line, c-myc ex pression was also decreased in response to doxorubicin incubation, but the expression of c-jun remained unchanged over the whole range of co ncentrations. In contrast, vincristine had no effect on the amounts of c-myc and c-jun mRNAs in either line. The effect of doxorubicin on th e mRNA levels of c-jun was also observed on the JUN proteins by immuno blotting, but the MYC protein levels remained unchanged upon doxorubic in treatment. There was a significant correlation between the levels o f c-myc and c-jun gene expression and the degree of growth inhibition induced by doxorubicin. In addition, doxorubicin induced a fragmentati on of DNA in sensitive cells, but not in resistant cells, thus reveali ng a resistance to apoptosis in this line. Doxorubicin-induced cell de ath did not appear to be mediated by p53 in either cell line. BIOCHEM PHARMACOL 55;12:1963-1971, 1998. (C) 1998 Elsevier Science Inc.