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, Fengzhi Li

Research output: Contribution to journalArticle

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Abstract

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 G 2/M cells were significantly increased at later times. Interestingly, 3 nM tamol 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 tamol-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.

Original languageEnglish (US)
Pages (from-to)15196-15203
Number of pages8
JournalJournal of Biological Chemistry
Volume279
Issue number15
DOIs
Publication statusPublished - Apr 9 2004

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ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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