Proteomic analysis reveals a novel role for the actin cytoskeleton in vincristine resistant childhood leukemia -: An in vivo study
Proteomic analysis reveals a novel role for the actin cytoskeleton in vincristine resistant childhood leukemia -: An in vivo study
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DOI：
10.1002/pmic.200500417
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发表时间：
2006-03-01
期刊：
影响因子：
3.4
通讯作者：
Kavallaris, M
中科院分区：
文献类型：
--
作者：
Verrills, NM;Liem, NL;Kavallaris, M
长春新碱（VCR）是一种用于治疗儿童急性淋巴细胞白血病（ALL）的抗微管药物，其内在或获得性耐药是一个主要的临床问题。使用临床相关的NOD/SCID小鼠ALL异种移植模型，我们确定了肌动蛋白和微管蛋白细胞骨架的改变与体内VCR耐药性有关。使用2-D DIGE结合MS鉴定了VCR敏感性ALL异种移植物和内源性或获得性VCR耐药异种移植物之间的蛋白表达改变。在显示表达改变的19种蛋白中，11种与肌动蛋白细胞骨架相关。肌动蛋白和/或微管蛋白结合蛋白凝溶胶蛋白、膜突蛋白、埃兹蛋白、原肌球蛋白、CAP-G、HSP 27、HSP 70、TCP-1和stathmin的表达改变与体内VCR耐药性相关。肌动蛋白调节蛋白凝溶胶蛋白增加获得性和耐药白血病证实免疫印迹和基因表达。主要的细胞骨架蛋白，γ-肌动蛋白，在VCR耐药的白血病异种移植物中下调;相反，β-肌动蛋白表达没有显著变化。这项研究提供了第一个证据的内在和后天的儿童白血病体内抗微管药物耐药性的肌动蛋白细胞骨架的作用，并强调了权力的2-D DIGE的耐药标志物的发现，药物蛋白质组学和信号通路在癌症。
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, gamma-actin, was down-regulated in the VCR-resistant leukemia xenografts; in contrast, there was no significant change in beta-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.