Abstract
Although apoptosis can be induced by the enforced expression of exogenously introduced c-myc genes, it is not clear whether overexpression resulting from the amplification of the resident c-myc gene in tumor cells is sufficient 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, respectively, of tumorigenic and non-tumorigenic clones isolated from the SW613-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 non-tumorigenic clones have a small number of copies and a lower level of expression of this gene. Analysis of c-myc mRNA level in cells cultured under low serum conditions indicated that the expression of the gene is tightly regulated by serum growth factors in non-tumorigenic B3 cells, whereas it is poorly regulated in tumorigenic 12A1 cells, the level of mRNAs remaining relatively high in serum-starved 12A1 cells. Under these conditions, 12A1 cells showed clear evidence of apoptosis, whereas B3 cells were completely refractory to the induction of apoptosis. Moreover, the study of cell lines derived from non-tumorigenic apoptosis-resistant clones following the introduction by transfection of exogenous c-myc gene copies showed that they have acquired an apoptosis-prone phenotype. Altogether, our results strongly suggest that deregulated c-myc expression due to high-level amplification confers an apoptosis-prone phenotype to tumor cells. The possible consequences of these observations for cancer therapy are discussed.
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Abbreviations
- BCIP:
-
5-bromochloro-3-indolyl phosphate
- DGGE:
-
denaturing gradient gel electrophoresis
- DMEM:
-
Dulbecco's modified Eagle medium
- NBT:
-
p-nitrotetrazolium blue
- PARP:
-
poly(ADP-ribose) polymerase
- PBS:
-
phosphate buffered saline
- SDS – PAGE:
-
sodium dodecyl sulphate-polyacrylamide gel electrophoresis
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Acknowledgements
We are greatly indebted to Dr G Poirier (Université Laval, Québec, Canada) for the monoclonal antibody C-2-10 and to Prof G Ranzani (IGM, Università di Pavia, Italy) for helpful discussions on p53 experiments. M Donzelli was supported by a fellowship from AIRC (Associazione Italiana per la Ricerca sul Cancro). C Negri and L Padovan are Telethon and Anna Villa Rusconi fellows, respectively. This work was supported in part by grants from the Association pour la Recherche sur le Cancer and from the Ligue Nationale contre le Cancer.
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Donzelli, M., Bernardi, R., Negri, C. et al. Apoptosis-prone phenotype of human colon carcinoma cells with a high level amplification of the c-myc gene. Oncogene 18, 439–448 (1999). https://doi.org/10.1038/sj.onc.1202309
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DOI: https://doi.org/10.1038/sj.onc.1202309
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