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Gene Expression and Mitotic Exit Induced by Microtubule-Stabilizing Drugs

¹ Department of Molecular Pharmacology
² Analytical Imaging Facility, Albert Einstein College of Medicine, Bronx, New York

To explore the molecular mechanisms underlying the actions of Taxol and the functionally related molecule epothilone B (EpoB), we have analyzed the gene expression profiles in A549 cells in response to increasing concentrations of these microtubule-stabilizing drugs. An almost identical expression pattern was observed in cells treated with either Taxol or EpoB. Low concentrations of the drugs induced aberrant mitosis including asymmetric and multipolar cell divisions. At drug concentrations that trigged G₂-M arrest, cells escaped from a prolonged mitotic arrest without cell division, resulting in tetraploid G₁ cells. This mitotic slippage is correlated with diminished expression of cdc2 kinase, topoisomerase II, BUB3, and BUB2-like protein 1, as well as with an increased expression of 14-3-3-. Poly(ADP-ribose) polymerase cleavage, an early indicator of apoptosis, occurred in cells undergoing mitotic slippage and in aneuploid cells resulting from aberrant mitosis. In contrast, cells arrested in mitosis demonstrated no signal for apoptosis but had an increased expression of survivin, an inhibitor of apoptosis. Induction of aneuploid or tetraploid G₁ cells was accompanied by increased expression of CD95, p21, and BTG2 that may contribute to cell death because their expression was diminished in an EpoB-resistant cell line. In contrast, expression of GADD45 and PTGF-ß could promote cell survival. We conclude that abnormal mitotic exit is required for apoptotic cell death induced by microtubule-stabilizing drugs.

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