The microtubule inhibiting agent epothilone B antagonizes glioma cell motility associated with reorganization of the actin-binding protein α-actinin 4
The microtubule inhibiting agent epothilone B antagonizes glioma cell motility associated with reorganization of the actin-binding protein α-actinin 4
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DOI：
10.3892/or.2011.1145
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发表时间：
2011-03-01
期刊：
影响因子：
4.2
通讯作者：
Quick, Quincy A.
中科院分区：
文献类型：
--
作者：
Henry, Whitney I.;Dubois, Juwen;Quick, Quincy A.
脑肿瘤细胞对正常脑组织的侵袭是临床诊断的胶质母细胞瘤复发和对治疗（手术、化疗、放疗）抵抗的主要促成因素。在这里，我们评估了微管抑制剂埃博霉素B对胶质母细胞瘤细胞运动的疗效，这是侵袭性胶质母细胞瘤的先决条件。使用细胞迁移试验和免疫荧光技术，我们证明，埃坡霉素B废除胶质母细胞瘤细胞的运动性作为一个结果，α-辅肌动蛋白4 redistribiton和细胞结构（前缘，应力纤维）的崩溃，它是与细胞迁移过程中。胶质母细胞瘤细胞中微管肌动蛋白交联因子的评价也揭示了埃博霉素B引起的这种细胞骨架交联蛋白的变化，类似于响应于埃博霉素B的α-辅肌动蛋白4的变化。我们在这项研究中已经证明，埃坡霉素B拮抗胶质母细胞瘤细胞的运动性，由于破坏细胞骨架结合蛋白，有助于保持细胞骨架丝状网络的结构组织。此外，我们提供了临床前证据表明埃坡霉素B对胶质母细胞瘤的作用不仅限于分裂肿瘤细胞的损伤，而且还靶向迁移和侵袭性胶质母细胞瘤细胞，这表明该药物具有潜在的临床益处，因为它能够靶向胶质母细胞瘤肿瘤块中的不同细胞程序。
Invasion of normal brain tissue by brain tumor cells is a major contributing factor to the recurrence and resistance of clinically diagnosed glioblastomas to therapy (surgery, chemotherapy, radiation). Here, we have assessed the efficacy of the microtubule inhibiting agent epothilone B on glioblastoma cell motility, a prerequisite cellular program of invasive glioblastomas. Using cell migration assays and immunofluorescence techniques we demonstrated that epothilone B abrogated glioblastoma cell motility as a consequence of a-actinin 4 redistristrubiton and the breakdown of cellular structures (leading edge, stress fibers) it is associated with during cell migration. Evaluation of the microtubule actin cross linking factor in glioblastoma cells also revealed epothilone B invoked changes in this cytoskeleton cross linking protein, resembling a-actinin 4 changes in response to epothilone B. We have demonstrated in this study that epothilone B antagonizes glioblastoma cell motility due to the disruption of cytoskeleton binding proteins that aide in preserving the structural organization of the cytoskeleton filamentous network. Furthermore, we provide preclincial evidence that epothilone B effects on glioblastomas are not limited to the impairment of dividing tumors cells but that it also targets migratory and invasive glioblastoma cells, suggesting that this agent has potential clinical benefit due to its ability to target divergent cellular programs in the glioblastoma tumor mass.