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Proteomic analysis reveals a novel role for the actin cytoskeleton in vincristine resistant childhood leukemia – An in vivo study
Author(s) -
Verrills Nicole M.,
Liem Natalia L.,
Liaw Tracy Y. E.,
Hood Brian D.,
Lock Richard B.,
Kavallaris Maria
Publication year - 2006
Publication title -
proteomics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.26
H-Index - 167
eISSN - 1615-9861
pISSN - 1615-9853
DOI - 10.1002/pmic.200500417
Subject(s) - gelsolin , ezrin , moesin , biology , cytoskeleton , actin cytoskeleton , cofilin , microbiology and biotechnology , cancer research , in vivo , actin , cell , biochemistry , genetics
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.