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 overexpresion antagonizes Fas/Fas ligand-mediated cell death. The mechanism by which Bcl-X_L influences Fas-mediated cell death is unclear. We have found that microtubule-damaging drugs (e.g. Paclitaxel) induce apoptosis in a Fas/FasL-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 caspase-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 activation of calcineurin, a calcium-dependent phosphatase that must dephosphorylate NFAT for it to move to the nucleus. The loop domain in Bcl-X_L can suppress the anti-apoptotic function of Bcl-X_L and may be a target for regulatory post-translational modifications. Upon phosphorylation, Bcl-X_L loses its ability to bind with calcineurin. Without NFAT nuclear translocation, the FasL gene is not transcribed. Thus, paclitaxel and other drugs that disturb microtubule function kill cells, at least in part, through the induction of FasL, and Bcl-X_L-mediated resistance to these agents is related to failure to induce FasL expression.