Forced Expression of Survivin-2B Abrogates Mitotic Cells and Induces Mitochondria-dependent Apoptosis by Blockade of Tubulin Polymerization and Modulation of Bcl-2, Bax, and Survivin

• Published in: The Journal of biological chemistry 2007-09, Vol.282 (37), p.27204-27214
• Main Authors: Ling, Xiang, Cheng, Qiuying, Black, Jennifer D., Li, Fengzhi
• Format: Article
• Language: English
• Subjects: Apoptosis; bcl-2-Associated X Protein - analysis; Caspase 8 - physiology; Cell Line; Humans; Inhibitor of Apoptosis Proteins; Microtubule-Associated Proteins - analysis; Microtubule-Associated Proteins - physiology; Mitochondria - physiology; Mitosis; Neoplasm Proteins - analysis; Neoplasm Proteins - physiology; Paclitaxel - pharmacology; Proto-Oncogene Proteins c-bcl-2 - analysis; Survivin; Tubulin - metabolism
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M705161200

It has been previously shown that both survivin and the survivin splice variant survivin-2B are localized in mitochondria. Whereas the mechanism involved in blockade of mitochondria-mediated apoptosis by survivin has been extensively studied, the role of survivin-2B in regulation of apoptosis has not been well defined. In the present study, we report that in addition to mitochondria, survivin-2B is also localized in the microtubule organization center (MTOC) and, in contrast to other survivin isoforms (i.e. survivin and survivin-ΔEx3), behaves as a proapoptotic molecule. We show that forced expression of survivin-2B blocks tubulin polymerization, ablates mitotic cells, and induces mitochondria-dependent apoptosis. The mitochondria-mediated apoptosis induced by survivin-2B was indicated by Smac release from mitochondria, activation of caspases 9 and 3, and loss of mitochondrial potential, while caspase-8 remained inactive. Further analysis of the mechanism for the mitochondria-associated events of apoptosis induced by forced expression of survivin-2B revealed down-regulation of the pro-survival factor Bcl-2 and up-regulation of the pro-apoptotic factor Bax in mitochondria, while the apoptosis-inducing factor (AIF) remains unchanged. Our studies further showed that taxol (paclitaxel) treatment of cancer cells not only up-regulates survivin but also down-regulates survivin-2B and that forced expression of survivin-2B sensitizes cells to taxol-induced cell growth inhibition and cell death, while silencing of endogenous survivin-2B transcripts by survivin-2B-specific siRNA made cells resistant to taxol treatment. These findings advance our current knowledge about survivin-2B and may help to develop novel approaches for cancer treatment.