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 death in human cell lines derived from acute leukemia, lymphoma, breast cancer, and prostate cancer. The results of this analysis indicate that drugs affecting the integrity of microtubules induce bc12 phosphorylation, whereas anticancer drugs damaging DNA do not. Comparison of the effects of taxol and its analogue, taxotere, indicates that taxotere is capable of inducing bcl2 phosphorylation and apoptotic cell death at 100-fold lower concentrations than taxol. Induction of cancer cell death through phosphorylation of bcl2 thus provides an opportunity not only for more refined targeting of therapeutic drugs but for understanding of an important pathway leading to apoptosis. Phosphorylation of bcl2 in drug-treated cancer cells occurs in G2-M, the phase of the cell cycle in which this class of drugs is active. No induction of bcl2 phosphorylation occurs in chronic lymphocytic leukemia cells that overexpress bcl2 but are blocked at G0-G1. Thus, prevention of polymerization or depolymerization of cellular microtubules by this class of cancer therapeutic drugs causes phosphorylation of bcl2, abrogating the normal antiapoptotic function of bcl2 and initiating the apoptotic program in the cycling cancer cells; these results are consistent with a normal physiological role of bcl2 as "guardian of microtubule integrity."
Haldar
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Kimmel Cancer Center, Jefferson Medical College, Philadelphia, Pennsylvania 19107, USA.
Basu
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Croce
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D000970:Antineoplastic Agents / Q000494:pharmacology*; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects*; D002908:Chronic Disease; D000077143:Docetaxel; D016195:G2 Phase; D006801:Humans; D007938:Leukemia / Q000378:metabolism / Q000473:pathology; D016393:Lymphoma, B-Cell / Q000188:drug therapy / Q000378:metabolism; D008297:Male; D008870:Microtubules / Q000187:drug effects*; D017239:Paclitaxel / Q000031:analogs & derivatives / Q000494:pharmacology; D010766:Phosphorylation; D011471:Prostatic Neoplasms / Q000188:drug therapy / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000187:drug effects* / Q000378:metabolism / Q000502:physiology; D043823:Taxoids; D014407:Tumor Cells, Cultured / Q000187:drug effects
D000970:Antineoplastic Agents; D000972:Antineoplastic Agents, Phytogenic; D019253:Proto-Oncogene Proteins c-bcl-2; D043823:Taxoids; D000077143:Docetaxel; D017239:Paclitaxel