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J. Biol. Chem., Vol. 278, Issue 46, 45082-45093, November 14, 2003

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Proteome Analysis of Vinca Alkaloid Response and Resistance in Acute Lymphoblastic Leukemia Reveals Novel Cytoskeletal Alterations^*

Nicole M. Verrills¶, Bradley J. Walsh, Gary S. Cobon, Peter G. Hains, and Maria Kavallaris||

From the Children's Cancer Institute Australia for Medical Research, High St. (P. O. Box 81), Randwick, New South Wales 2031 and the Australian Proteome Analysis Facility, Macquarie University, Sydney, New South Wales 2109, Australia

Vinca alkaloids are used widely in the treatment of both childhood and adult cancers. Their cellular target is the -tubulin subunit of /-tubulin heterodimers, and they act to inhibit cell division by disrupting microtubule dynamics. Despite the effectiveness of these agents, drug resistance is a major clinical problem. To identify the underlying mechanisms behind vinca alkaloid resistance, we have performed high resolution differential proteome analysis. Treatment of drug-sensitive human leukemia cells (CCRF-CEM) with vincristine identified numerous proteins involved in the cellular response to vincristine. In addition, differential protein expression was analyzed in leukemia cell lines selected for resistance to vincristine (CEM/VCR R) and vinblastine (CEM/VLB100). This combined proteomic approach identified 10 proteins altered in both vinca alkaloid response and resistance: -tubulin, -tubulin, actin, heat shock protein 90, 14-3-3, 14-3-3, L-plastin, lamin B1, heterogeneous nuclear ribonuclear protein-F, and heterogeneous nuclear ribonuclear protein-K. Several of these proteins have not previously been associated with drug resistance and are thus novel targets for elucidation of resistance mechanisms. In addition, seven of these proteins are associated with the tubulin and/or actin cytoskeletons. This study provides novel insights into the interrelationship between the microtubule and microfilament systems in vinca alkaloid resistance.

Received for publication, April 2, 2003 , and in revised form, August 20, 2003.

^* This work was supported in part by the Children's Cancer Institute Australia for Medical Research, which is affiliated with the University of New South Wales and Sydney Children's Hospital, and by grants from the National Health and Medical Research Council, New South Wales Cancer Council, and Cure Cancer Australia Foundation. This research has been facilitated by access to the Australian Proteome Analysis Facility established under the Australian Governments' Major National Research Facilities Program. 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.

The on-line version of this article (available at http://www.jbc.org) contains Figs. S1 and S2 and Table S1.

^¶ A recipient of an Australian Postgraduate Award and an Australian Proteome Analysis Facility Supplementary Award.

^|| To whom correspondence should be addressed. Tel.: 61-2-9382-1823; Fax: 61-2-9382-1850; E-mail: m.kavallaris{at}unsw.edu.au.

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