BCL2 IS THE GUARDIAN OF MICROTUBULE INTEGRITY

We have investigated the ability of several drugs commonly used in the treatment of human cancer to induce bcl2 phosphorylation and cell dea th in human cell lines derived from acute leukemia, lymphoma, breast c ancer, and prostate cancer, The results of this analysis indicate that drugs affecting the integrity of microtubules induce bcl2 phosphoryla tion, whereas anticancer drugs damaging DNA do not. Comparison of the effects of taxol and its analogue, taxotere, indicates that taxotere i s capable of inducing bcl2 phosphorylation and apoptotic cell death at 100-fold lower concentrations than taxol, Induction of cancer cell de ath through phosphorylation of bcl2 thus provides an opportunity not o nly for more refined targeting of therapeutic drugs but for understand ing of an important pathway leading to apoptosis. Phosphorylation of b cl2 in drug-treated cancer cells occurs in G(2)-M, the phase of the ce ll cycle in which this class of drugs is active, No induction of bcl2 phosphorylation occurs in chronic lymphocytic leukemia cells that over express bcl2 but are blocked at G(0)-G(1). Thus, prevention of polymer ization or depolymerization of cellular microtubules by this class of cancer therapeutic drugs causes phosphorylation of bcl2, abrogating th e normal antiapoptotic function of bcl2 and initiating the apoptotic p rogram in the cycling cancer cells; these results are consistent with a normal physiological role of bcl2 as ''guardian of microtubule integ rity.''