Bcl-2 inhibits calcineurin-mediated Fas ligand expression in antitumor drug-treated baby hamster kidney cells

It is well known that human leukemia cells, such as HL-60 and U937 are sens itive to antitumor drugs, but human normal lung fibroblasts, such as WI-38 cells are resistant to the drugs. However, the mechanisms of the different responses to apoptosis in these cell lines remain unclear. We report here t hat an increase of Fas and Fas Ligand (FasL) expression was required for an titumor drug-induced apoptosis in W1-38 and baby hamster kidney (BHK) cells , but not in HL-60 cells. Then, we used BHK cells transfected with the bcl- 2 gene to investigate the involvement of complex formation of Bcl-2 and cal cineurin, Calcineurin was imported to the nucleus in response to the drug t reatment, Overexpression of Bcl-2 and cyclosporin A treatment inhibited the nuclear import and Fast expression, and as a result, both inhibited apopto sis, although a caspase inhibitor, z-Asp-CH2- DCB, suppressed the drug-indu ced apoptosis, it failed to inhibit the drug-induced expression of Fas and Fast. These findings suggest that initially the Fas/FasL system is activate d by calcineurin-dependent transcription followed by activation of the down stream caspase cascade resulting in antitumor drug-induced apoptosis in BHK cells, but not in HL-60 cells. Furthermore, Bcl-2 inhibits the nuclear imp art of calcineurin and suppresses calcineurin-mediated Fast expression duri ng antitumor drug-induced apoptosis.