CHARACTERIZATION OF C-MYC-TRANSFORMED RAT FIBROBLASTS RESISTANT TO APOPTOSIS INDUCED BY GROWTH-FACTOR DEPRIVATION

Under appropriate conditions (e.g., growth factor withdrawal), the der egulated expression of c-myc in rodent fibroblasts leads to substantia l cell death due to apoptosis. To better understand this process, we s elected for c-myc-transformed RataA fibroblasts that were resistant to growth factor deprivation-induced cell death. One clonal isolate exhi bited prolonged survival in serum-free medium and displayed reduced le vels of apoptosis-related DNA fragmentation. These cells were also res istant to induction of apoptosis by the protein kinase inhibitor staur osporine. They retained a transformed cell phenotype and expressed the proviral. human c-myc allele in an unaltered fashion, strongly indica ting that the mutation of a cellular gene other than c-myc accounts fo r the apoptosis-resistant phenotype. The results of somatic cell hybri d analysis of this cell line are consistent with a recessive mutation. Our findings suggest a novel mechanism for abrogation of apoptosis in neoplastic cells and provide a model system for the study of its role in tumorigenesis and resistance to antineoplastic therapy. (C) 1996 A cademc Press, Inc.