Parkin regulates paclitaxel sensitivity in breast cancer via a microtubule-dependent mechanism
Parkin regulates paclitaxel sensitivity in breast cancer via a microtubule-dependent mechanism
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DOI：
10.1002/path.2512
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发表时间：
2009-05-01
影响因子：
7.3
通讯作者：
Zhou, Jun
中科院分区：
文献类型：
--
作者：
Wang, Hongxia;Liu, Bingbing;Zhou, Jun
Parkin是由Parkin基因（也称为PARK 2，位于6q25.2-q27）编码的E3泛素连接酶，并参与帕金森病的发病机制和癌症的发展。最近，帕金已被证明与微管细胞骨架相互作用。然而，帕金森微管轴的生物学意义一直探索甚少。在这项研究中，我们首次报道了帕金通过微管依赖性机制调节乳腺癌化疗药物紫杉醇的敏感性。我们的数据表明，帕金结合到微管的外表面，并增加紫杉醇微管相互作用，从而增强紫杉醇诱导的微管组装和稳定。我们的数据进一步表明，帕金促进紫杉醇的活性，引发多核和凋亡，使乳腺癌细胞对这种药物更敏感。此外，Parkin表达与肿瘤对术前含紫杉醇化疗的病理反应相关。此外，Parkin的表达还与乳腺癌细胞原代培养物中紫杉醇的敏感性相关。我们的研究结果确定帕金作为一种新的调解人紫杉醇敏感性在乳腺癌。此外，我们的研究表明，患有高帕金水平肿瘤的患者更有可能从含紫杉醇的方案中获益。版权所有（C）2009大不列颠和爱尔兰病理学会。出版社：John Wiley & Sons，Ltd
Parkin is an E3 ubiquitin ligase encoded by the Parkin gene (also called PARK2, located at 6q25.2-q27) and is involved in the pathogenesis of Parkinson's disease and the development of cancer. Recently, Parkin has been demonstrated to interact with the microtubule cytoskeleton. However, the biological implication of the Parkin-microtubule axis has been poorly explored. In this study, we report for the first time that Parkin modulates sensitivity of the chemotherapeutic agent paclitaxel in breast cancer, via a microtubule-dependent mechanism. Our data reveal that Parkin binds to the outer surface of microtubules and increases paclitaxel-microtubule interaction, resulting in enhanced paclitaxel-induced microtubule assembly and stabilization. Our data further show that Parkin promotes the activity of paclitaxel to trigger multi nucleation and apoptosis, rendering breast cancer cells more sensitive to this drug. Moreover, Parkin expression correlates with the pathological response of tumours to preoperative paclitaxel-containing chemotherapy. In addition, expression of Parkin also correlates with the sensitivity of paclitaxel in primary cultures of breast cancer cells. Our results identify Parkin as a novel mediator of paclitaxel sensitivity in breast cancer. In addition, our study suggests that patients harbouring tumours with high Parkin level would be more likely to benefit from paclitaxel-containing regimens. Copyright (C) 2009 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.