Apoptosis-prone phenotype of human colon carcinoma cells with a high levelamplification of the c-myc gene

Although apoptosis can be induced by the enforced expression of exogenously introduced c-myc genes, it is not clear whether overexpression resulting f rom the amplification of the resident c-myc gene in tumor cells is sufficie nt to induce apoptosis, We have investigated the relationship between c-myc gene amplification and the propensity of tumor cells to undergo apoptosis, using the SW613-12A1 and SW613-B3 cell lines, which are representatives, r espectively, of tumorigenic and nontumorigenic clones isolated from the SW6 13-S human colon carcinoma cell line. Tumorigenic clones are characterized by a high level of amplification and expression of the c-myc gene, whereas cells of nontumorigenic clones have a small number of copies and a lower le vel of expression of this gene. Analysis of c-myc mRNA level in cells cultu red under low serum conditions indicated that the expression of the gene is tightly regulated by serum growth factors in non-tumorigenic B3 cells, whe reas it is poorly regulated in tumorigenic 12A1 cells, the level of mRNAs r emaining relatively high in serum-started 12A1 cells, Under these condition s, 12A1 cells showed clear evidence of apoptosis, whereas B3 cells were com pletely refractory to the induction of apoptosis, Moreover, the study of ce ll lines derived from nontumorigenic apoptosis-resistant clones following t he introduction by transfection of exogenous c-myc gene copies showed that they have acquired an apapoptosis-prone phenotype. Altogether, our results strongly suggest that deregulated c-myc expression due to high-level amplif ication confers an apoptosis-prone phenotype to tumor cells. The possible c onsequences of these observations for cancer therapy are discussed.