Inhibition of Spleen Tyrosine Kinase Potentiates Paclitaxel-Induced Cytotoxicity in Ovarian Cancer Cells by Stabilizing Microtubules.
Inhibition of Spleen Tyrosine Kinase Potentiates Paclitaxel-Induced Cytotoxicity in Ovarian Cancer Cells by Stabilizing Microtubules.
复制标题
脾酪氨酸激酶的抑制通过稳定微管通过稳定卵巢癌细胞中紫杉醇诱导的细胞毒性。
DOI：
10.1016/j.ccell.2015.05.009
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发表时间：
2015-07-13
期刊：
影响因子：
50.3
通讯作者：
Shih IeM
中科院分区：
文献类型：
--
作者：
Yu Y;Gaillard S;Phillip JM;Huang TC;Pinto SM;Tessarollo NG;Zhang Z;Pandey A;Wirtz D;Ayhan A;Davidson B;Wang TL;Shih IeM
化疗耐药是长期缓解的主要障碍，克服耐药的有效策略将对临床产生重大影响。我们在这里报道，在紫杉醇/卡铂治疗后，卵巢癌上调了脾酪氨酸激酶(SYK)和磷酸化SYK的表达。在体外，紫杉醇耐药细胞表达较高的SYK，并且磷酸化SYK/SYK比值与紫杉醇耐药呈正相关。抑制物灭活SYK或基因敲除致敏体内外紫杉醇细胞毒性。对紫杉醇耐药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增强了紫杉醇耐药肿瘤细胞的微管稳定性，否则这些细胞是不敏感的。因此，靶向SYK通路是一种有前景的增强紫杉醇反应的策略。
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 here that after paclitaxel/carboplatin treatment, ovarian carcinomas have upregulated 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.