Bcl-2-mediated drug resistance: Inhibition of apoptosis by blocking nuclear factor of activated T lymphocytes (NFAT)-induced Fas ligand transcription

Bcl-2 inhibits apoptosis induced by a variety of stimuli, including chemoth erapy drugs and glucocorticoids. It is generally accepted that Bcl-2 exerts its antiapoptotic effects mainly by dimerizing with proapoptotic members o f the Bcl-2 family such as Bar and Bad. However, the mechanism of the antia poptotic effects is unclear. Paclitaxel and other drugs that disturb microt ubule dynamics kill cells in a Fas/Fas ligand (FasL)-dependent manner; anti body to Fast. inhibits paclitaxel-induced apoptosis. We have found that Bcl -2 overexpression leads to the prevention of chemotherapy (paclitaxel)-indu ced expression of Fast and blocks paclitaxel-induced apoptosis. The mechani sm of this effect is that Bcl-2 prevents the nuclear translocation of NFAT (nuclear factor of activated T lymphocytes, a transcription factor activate d by microtubule damage) by binding and sequestering calcineurin, a calcium -dependent phosphatase that must dephosphorylate NFAT to move to the nucleu s. Without NFAT nuclear translocation, the Fast gene is not transcribed. Th us, it appears that paclitaxel and other drugs that disturb microtubule fun ction kill cells at least in part through the induction of FasL. Furthermor e, Bcl-2 antagonizes drug-induced apoptosis by inhibiting calcineurin activ ation, blocking NFAT nuclear translocation, and preventing Fast expression. The effects of Bcl-2 can be overcome, at least partially, through phosphor ylation of Bcl-2. Phosphorylated Bcl-2 cannot bind calcineurin, and NFAT ac tivation, Fast expression, and apoptosis can occur after Bcl-2 phosphorylat ion.