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J. Biol. Chem., Vol. 279, Issue 15, 15196-15203, April 9, 2004

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Induction of Survivin Expression by Taxol (Paclitaxel) Is an Early Event, Which Is Independent of Taxol-mediated G₂/M Arrest^*

Xiang Ling, Ralph J. Bernacki, Michael G. Brattain, and Fengzhi Li

From the Department of Pharmacology and Therapeutics, Grace Cancer Drug Center, Roswell Park Cancer Institute, Buffalo, New York 14263

Survivin is a novel anti-apoptotic protein that is highly expressed in cancer but is undetectable in most normal adult tissues. It was reported that taxol-mediated mitotic arrest of cancer cells is associated with survivin induction, which preserves a survival pathway and results in resistance to taxol. In this study, we provide new evidence that induction of survivin by taxol is an early event and is independent of taxol-mediated G₂/M arrest. Taxol treatment of MCF-7 cells rapidly up-regulated survivin expression (3.5–15-fold) within 4 h without G₂/M arrest. Lengthening the treatment of cells (48 h) with taxol resulted in decreased survivin expression in comparison with early times following taxol treatment, although G₂/M cells were significantly increased at later times. Interestingly, 3 nM taxol induces survivin as effectively as 300 nM and more effectively than 3000 nM. As a result, 3 nM taxol is ineffective at inducing cell death. However, inhibition of taxol-mediated survivin induction by small interfering RNA significantly increased taxol-mediated cell death. Taxol rapidly activated the phosphatidylinositol 3-kinase/Akt and MAPK pathways. Inhibition of these pathways diminished survivin induction and sensitized cells to taxol-mediated cell death. A cis-acting DNA element upstream of -1430 in the survivin pLuc-2840 construct is at least partially responsible for taxol-mediated survivin induction. Together, these data show, for the first time, that taxol-mediated induction of survivin is an early event and independent of taxol-mediated G₂/M arrest. This appears to be a new mechanism for cancer cells to evade taxol-induced apoptosis. Targeting this survival pathway may result in novel approaches for cancer therapeutics.

Received for publication, October 3, 2003 , and in revised form, December 10, 2003.

^* This work was supported in part by Concern Foundation (Beverly Hill, CA), Elsa U. Pardee Foundation (Midland, MI), and Roswell CCSG Development Funds from NCI Comprehensive Cancer Center Core Grant CA16056. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

To whom correspondence should be addressed: Dept. of Pharmacology and Therapeutics, Roswell Park Cancer Institute (RPCI), Elm & Carlton St., Buffalo, NY 14263. Tel.: 716-845-4398; Fax: 716-845-8857; E-mail: fengzhi.li{at}roswellpark.org.

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