- Title
- Proteomic analysis reveals a novel role for the actin cytoskeleton in vincristine resistant childhood leukemia: an in vivo study
- Creator
- Verrills, Nicole M.; Liem, Natalia L.; Liaw, Tracey Y. E.; Hood, Brian D.; Lock, Richard B.; Kavallaris, Maria
- Relation
- Proteomics Vol. 6, Issue 5, p. 1681-1694
- Publisher Link
- http://dx.doi.org/10.1002/pmic.200500417
- Publisher
- Wiley - VCH Verlag GmbH & Co.
- Resource Type
- journal article
- Date
- 2006
- Description
- 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.
- Subject
- actin; drug resistance; leukaemia; vincristine
- Identifier
- uon:1006
- Identifier
- http://hdl.handle.net/1959.13/26650
- Identifier
- ISSN:1615-9853
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