Changes in glucocorticoid-induced apoptosis and in expression of Bcl-2 protein during long-term culture of thymic lymphoma.
Lymphomagenesis is a multistep process progressively freeing transformed thymocytes from external regulatory signals, i.e. thymic developmental program controlling growth, differentiation or apoptosis. Here we report that cells of thymic lymphoma overexpressing Ras/Raf proteins, initially resistant to TCR-dependent apoptosis but sensitive to dexamethasone- and etoposide-induced cell death, became insensitive to dexamethasone after long-time culture. That transition correlated with a strong increase in the expression of the anti-apoptotic Bcl-2 protein. Interestingly, lymphoma cells were still sensitive to p53-mediated apoptosis induced by etoposide. It suggests that the anti-apoptotic activity of Bcl-2 is correlated with a resistance to glucocorticoid-induced apoptosis but not to p53-mediated apoptosis. The sequence of mutations in the process of lymphomagenesis seems to be composed of at least 3 main hits which equip the cells with independence from external mitogenic signals (activation of Ras/Raf), resistance to inducers of apoptosis (activation of Bcl-2) and generation of cellular heterogeneity (deletion of p53) important in tumor progression.
Kobzdej
M
M
Laboratory of Cellular Immunology, Institute of Immunology and Experimental Therapy, Polish Academy of Sciences, Wroclaw.
Matuszyk
J
J
Zioło
E
E
Strzadała
L
L
D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D003907:Dexamethasone / Q000494:pharmacology*; D004351:Drug Resistance / Q000235:genetics; D016158:Genes, p53; D006801:Humans; D016399:Lymphoma, T-Cell / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D051379:Mice; D008810:Mice, Inbred C57BL; D009154:Mutation; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism*; D013953:Thymus Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D014407:Tumor Cells, Cultured
D019253:Proto-Oncogene Proteins c-bcl-2; D003907:Dexamethasone