抑制脾酪氨酸激酶通过稳定微管增强紫杉醇对卵巢癌细胞的细胞毒性。
Inhibition of Spleen Tyrosine Kinase Potentiates Paclitaxel-Induced Cytotoxicity in Ovarian Cancer Cells by Stabilizing Microtubules.
作者信息
Yu Yu, Gaillard Stephanie, Phillip Jude M, Huang Tai-Chung, Pinto Sneha M, Tessarollo Nayara G, Zhang Zhen, Pandey Akhilesh, Wirtz Denis, Ayhan Ayse, Davidson Ben, Wang Tian-Li, Shih Ie-Ming
机构信息
Department of Pathology and Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins Medical Institutions, Baltimore, MD 21205, USA.
Department of Chemical and Biomolecular Engineering, Physical Sciences-Oncology Center, and Institute for NanoBioTechology, Johns Hopkins University, Baltimore, MD 21218, USA.
出版信息
Cancer Cell. 2015 Jul 13;28(1):82-96. doi: 10.1016/j.ccell.2015.05.009. Epub 2015 Jun 18.
Resistance to chemotherapy represents a major obstacle for long-term remission, and effective strategies to overcome drug resistance would have significant clinical impact. We report that recurrent ovarian carcinomas after paclitaxel/carboplatin treatment have higher levels of spleen tyrosine kinase (SYK) and phospho-SYK. In vitro, paclitaxel-resistant cells expressed higher SYK, and the ratio of phospho-SYK/SYK positively associated with paclitaxel resistance in ovarian cancer cells. Inactivation of SYK by inhibitors or gene knockdown sensitized paclitaxel cytotoxicity in vitro and in vivo. Analysis of the phosphotyrosine proteome in paclitaxel-resistant tumor cells revealed that SYK phosphorylates tubulins and microtubule-associated proteins. Inhibition of SYK enhanced microtubule stability in paclitaxel-resistant tumor cells that were otherwise insensitive. Thus, targeting SYK pathway is a promising strategy to enhance paclitaxel response.
对化疗的耐药性是长期缓解的主要障碍，克服耐药性的有效策略将产生重大临床影响。我们报告称，接受紫杉醇/卡铂治疗后的复发性卵巢癌中脾酪氨酸激酶（SYK）和磷酸化SYK水平较高。在体外，耐紫杉醇细胞表达较高的SYK，磷酸化SYK/SYK的比率与卵巢癌细胞中的紫杉醇耐药性呈正相关。通过抑制剂或基因敲低使SYK失活可在体外和体内增强紫杉醇的细胞毒性。对耐紫杉醇肿瘤细胞中磷酸酪氨酸蛋白质组的分析表明，SYK使微管蛋白和微管相关蛋白磷酸化。抑制SYK可增强原本不敏感的耐紫杉醇肿瘤细胞中的微管稳定性。因此，靶向SYK通路是增强紫杉醇反应的一种有前景的策略。
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