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J. Biol. Chem., Vol. 280, Issue 13, 12902-12907, April 1, 2005

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III-Tubulin Induces Paclitaxel Resistance in Association with Reduced Effects on Microtubule Dynamic Instability^*

Kathy Kamath, Leslie Wilson, Fernando Cabral, and Mary Ann Jordan¶

From the Department of Molecular, Cellular, and Developmental Biology and the Neuroscience Research Institute, University of California Santa Barbara, Santa Barbara, California 93106 and the Department of Integrative Biology and Pharmacology, University of Texas Medical School, Houston, Texas 77030

The development of resistance to paclitaxel in tumors is one of the most significant obstacles to successful therapy. Overexpression of the III-tubulin isotype has been associated with paclitaxel resistance in a number of cancer cell lines and in tumors, but the mechanism of resistance has remained unclear. Paclitaxel inhibits cancer cell proliferation by binding to the -subunit of tubulin in microtubules and suppressing microtubule dynamic instability, leading to mitotic arrest and cell death. We hypothesized that III-tubulin overexpression induces resistance to paclitaxel either by constitutively enhancing microtubule dynamic instability in resistant cells or by rendering the microtubules less sensitive to the suppression of dynamics by paclitaxel. Using Chinese hamster ovary cells that inducibly overexpress either I- or III-tubulin, we analyzed microtubule dynamic instability during interphase by microinjection of rhodamine-labeled tubulin and time-lapse fluorescence microscopy. In the absence of paclitaxel, there were no differences in any aspect of dynamic instability between the two -tubulin-overexpressing cell types. However, in the presence of 150 nM paclitaxel, dynamic instability was suppressed to a significantly lesser extent (suppressed only 12%) in cells overexpressing III-tubulin than in cells overexpressing similar levels of I-tubulin (suppressed 47%). The results suggest that overexpression of III-tubulin induces paclitaxel resistance by reducing the ability of paclitaxel to suppress microtubule dynamics. The results also suggest that endogenous regulators of microtubule dynamics may differentially interact with individual tubulin isotypes, supporting the idea that differential expression of tubulin isotypes has functional consequences in cells.

Received for publication, December 22, 2004 , and in revised form, January 28, 2005.

^* This work was supported by NCI, National Institutes of Health Grant CA57291. 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. Tel.: 805-893-5317; E-mail: jordan{at}lifesci.ucsb.edu.

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