Open AccessBcl‐2 Inhibits Calcineurin‐mediated Fas Ligand Expression in Antitumor Drug‐treated Baby Hamster Kidney Cells
Author(s) -
Simizu Siro,
Shibasaki Futoshi,
Osada Hiroyuki
Publication year - 2000
Publication title -
japanese journal of cancer research
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.035
H-Index - 141
eISSN - 1349-7006
pISSN - 0910-5050
DOI - 10.1111/j.1349-7006.2000.tb01003.x
Subject(s) - fas ligand , calcineurin , apoptosis , baby hamster kidney cell , transfection , cancer research , fas receptor , cell culture , microbiology and biotechnology , biology , programmed cell death , medicine , transplantation , biochemistry , genetics
It is well known that human leukemia cells, such as HL‐60 and U937 are sensitive 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 that an increase of Fas and Fas ligand (FasL) expression was required for antitumor druginduced apoptosis in WI‐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 calcineurin. Calcineurin was imported to the nucleus in response to the drug treatment. Overexpression of Bcl‐2 and cyclosporin A treatment inhibited the nuclear import and FasL expression, and as a result, both inhibited apoptosis. Although a caspase inhibitor, z‐Asp‐CH 2 ‐DCB, suppressed the drug‐induced apoptosis, it failed to inhibit the drug‐induced expression of Fas and FasL. These findings suggest that initially the Fas/FasL system is activated by calcineurindependent transcription followed by activation of the downstream caspase cascade resulting in antitumor drug‐induced apoptosis in BHK cells, but not in HL‐60 cells. Furthermore, Bcl‐2 inhibits the nuclear import of calcineurin and suppresses calcineurin‐mediated FasL expression during antitumor drug‐induced apoptosis.