Please use this identifier to cite or link to this item: http://hdl.handle.net/1959.13/26650
- Proteomic analysis reveals a novel role for the actin cytoskeleton in vincristine resistant childhood leukemia: an in vivo study
Verrills, Nicole M.;
Liem, Natalia L.;
Liaw, Tracey Y. E.;
Hood, Brian D.;
Lock, Richard B.;
- Intrinsic or acquired resistance to vincristine (VCR), an antimicrotubule agent used in the treatment of childhood acute lymphoblastic leukemia (ALL), is a major clinical problem. Using a clinically relevant NOD/SCID mouse xenograft model of ALL, we established that alterations in the actin and tubulin cytoskeleton are involved in in vivo VCR resistance. Altered protein expression between VCR-sensitive ALL xenografts, and xenografts with intrinsic or acquired VCR resistance, was identified using 2-D DIGE coupled with MS. Of the 19 proteins displaying altered expression, 11 are associated with the actin cytoskeleton. Altered expression of the actin- and/or tubulin-binding proteins gelsolin, moesin, ezrin, tropomyosin, CAP-G, HSP27, HSP70, TCP-1, and stathmin were associated with in vivo VCR resistance. The actin-regulating protein gelsolin was increased in both acquired and resistant leukemia as confirmed by immunoblotting and gene expression. The major cytoskeletal protein, γ-actin, was down-regulated in the VCR-resistant leukemia xenografts; in contrast, there was no significant change in β-actin expression. This study provides the first evidence for a role of the actin cytoskeleton in intrinsic and acquired in vivo antimicrotubule drug resistance in childhood leukemia and highlights the power of 2-D DIGE for the discovery of resistance markers, pharmacoproteomics, and signaling pathways in cancer.
- Proteomics Vol. 6, Issue 5, p. 1681-1694
- Publisher Link
- Wiley - VCH Verlag GmbH & Co.
- Resource Type
- journal article