Inhibition of drug-induced Fas ligand transcription and apoptosis by Bcl-X-L

Fas/Fas ligand system triggers apoptosis in many cell types. Bcl-X-L overex presion antagonizes Fas/Fas ligand-mediated cell death. The mechanism by wh ich Bcl-X-L influences Fas-mediated cell death is unclear. We have found th at microtubule-damaging drugs (e.g. Paclitaxel) induce apoptosis in a Fas/F asL-dependent manner. Inhibition of Fas/FasL pathway by anti-FasL antibody, mutant Fas or a dominant negative FADD blocks paclitaxel-induced apoptosis . Paclitaxel induced apoptosis through activation of both caspase-8 and cas pase-3. Overexpression of Bcl-X-L leads to inhibition of paclitaxel-induced FasL expression and apoptosis. Bcl-X-L prevents the nuclear translocation of NFAT (nuclear factor of activated T lymphocytes) by inhibiting the activ ation of calcineurin, a calcium-dependent phosphatase that must dephosphory late NFAT for it to move to the nucleus. The loop domain in Bcl-X-L can sup press the anti-apoptotic function of Bcl-X-L and may be a target for regula tory post-translational modifications. Upon phosphorylation, Bcl-X-L loses its ability to bind with calcineurin. Without NFAT nuclear translocation, t he FasL gene is not transcribed. Thus, paclitaxel and other drugs that dist urb microtubule function kill cells, at least in part, through the inductio n of FasL, and Bcl-X-L-mediated resistance to these agents is related to fa ilure to induce FasL expression.