Displacement of Bim by Bmf and Puma rather than increase in Bim level mediates paclitaxel-induced apoptosis in breast cancer cells.
Taxanes exert their antitumor effect through stabilizing microtubule dynamics and initiating G2/M arrest in cancer cells followed by apoptotic cell death. However, the signaling pathways that connect paclitaxel-induced microtubule perturbation to mitochondrial outer membrane permeabilization and cytochrome c release are not well characterized. Here, we show that in breast cancer cells, paclitaxel induces a novel displacement mechanism: prodeath BH3-only proteins Bmf and Puma competitively displace prodeath BH3-only protein Bim from antiapoptotic proteins to activate Bax and Bak and commit the cell to apoptotic death. Bim and either Puma or Bmf are required for paclitaxel toxicity. Although prior mechanisms of apoptosis induced by taxol have focused on changes in Bim levels, we find that an increase is not required for paclitaxel killing of breast cancer cells. Rather, competitive displacement of Bim from antiapoptotic proteins is the important step committing the cell to death. This novel mechanism suggests the potential usage of novel therapies targeted at altering BH3-only protein heterodimerization.
Kutuk
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Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02115, USA.
Letai
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D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism*; D000972:Antineoplastic Agents, Phytogenic / Q000627:therapeutic use / Q000633:toxicity*; D017209:Apoptosis; D051017:Apoptosis Regulatory Proteins / Q000235:genetics / Q000378:metabolism*; D000072224:Bcl-2-Like Protein 11; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D045744:Cell Line, Tumor; D019281:Dimerization; D005260:Female; D006801:Humans; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D008928:Mitochondria / Q000378:metabolism; D017239:Paclitaxel / Q000627:therapeutic use / Q000633:toxicity*; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D034622:RNA Interference; D034741:RNA, Small Interfering
D048868:Adaptor Proteins, Signal Transducing; D000972:Antineoplastic Agents, Phytogenic; D051017:Apoptosis Regulatory Proteins; C438378:BBC3 protein, human; C000606775:BCL2L11 protein, human; C486655:BMF protein, human; D000072224:Bcl-2-Like Protein 11; D008565:Membrane Proteins; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D034741:RNA, Small Interfering; D017239:Paclitaxel