Abstract
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-DeltaEx3), 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.
Highlights
The mitotic survival checkpoint and mitochondria-mediated apoptosis control (3, 5)
We found that EGFP-survivin-2B colocalizes with the microtubule organization center (MTOC, Fig. 2A, arrow) while EGFP expression was evenly distributed in the cell (Fig. 3A)
Forced Expression of Survivin-2B Results in Down-regulation of Bcl-2 and Survivin but Up-regulation of Bax in Mitochondria, without Affecting Mitochondria-localized apoptosis-inducing factor (AIF) (Apoptosis-inducing Factor) Expression—To further explore the mechanism by which survivin-2B triggers activation of the mitochondrial cell death pathway, we examined whether forced expression of survivin-2B in mitochondria is able to modulate the expression of Bcl-2 family proteins
Summary
The mitotic survival checkpoint and mitochondria-mediated apoptosis control (3, 5). During mitosis, survivin is up-regulated and binds to the mitotic apparatus to control a mitotic survival checkpoint (1, 2) through interaction with and phosphorylation by the cyclin-dependent Cdc kinase on the mitotic apparatus (6, 7). Whereas the function of survivin has been extensively studied (3–5, 9 –11), the role of its splice variant survivin-2B in apoptosis control has not been well defined (9, 10). Survivin-2B expression is dominant in benign brain tumors in comparison with malignant tumors of the brain (16) and, in lung cancer cells, relatively high level expression of survivin-2B is significantly associated with the patient category of “no relapse and alive” (17). These observations argue that survivin-2B plays an inhibitory role in cancer development. We propose that survivin-2B may represent a novel tumor suppressor molecule, and analysis of its regulation and function mechanism may reveal new approaches for cancer treatment
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