Rack1 mediates Src binding to drug transporter P-glycoprotein and modulates its activity through regulating Caveolin-1 phosphorylation in breast cancer cells
Rack1 mediates Src binding to drug transporter P-glycoprotein and modulates its activity through regulating Caveolin-1 phosphorylation in breast cancer cells
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Rack1 介导 Src 与药物转运蛋白 P-糖蛋白的结合，并通过调节乳腺癌细胞中的 Caveolin-1 磷酸化来调节其活性
DOI：
10.1038/s41419-019-1633-y
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发表时间：
2019-05-21
影响因子：
9
通讯作者：
Zhang, Fei
中科院分区：
文献类型：
--
作者：
Fan, Yanling;Si, Weiyao;Zhang, Fei
化疗失败和多药耐药（MDR）的出现是局部晚期和转移性乳腺癌有效治疗的主要障碍。药物转运蛋白P-糖蛋白（P-gp）在癌细胞中的过度表达是导致MDR的主要原因之一，因为它能够将抗癌药物外排到细胞外。虽然调节P-gp表达的信号节点已被深入研究，但P-gp转运活性的调节机制仍不清楚。在此，我们报道了Rack 1和酪氨酸激酶Src通过调节P-gp的转运功能而不改变其蛋白水平来赋予耐药性。我们提供的证据表明，Rack1和Src调节P-gp的活性，通过调节小窝蛋白-1（Cav1）的磷酸化。重要的是，Rack1作为一个信号中枢，介导Src与P-gp的结合，从而促进Src对Cav1的磷酸化，消除Cav1对P-gp的抑制作用。综上所述，我们的研究结果表明Rack1和Src在耐药细胞中调节P-gp活性的关键作用。我们的研究结果也提供了新的见解调节P-gp转运活性的机制。Rack1可能是开发逆转耐药性的有效疗法的新靶点。
The failure of chemotherapy and the emergence of multidrug resistance (MDR) are the major obstacles for effective therapy in locally advanced and metastatic breast cancer. Overexpression of the drug transporter P-glycoprotein (P-gp) in cancer cells is one of the main causes of MDR due to its ability to efflux anticancer drugs out of cells. Although the signaling node that regulates the expression of P-gp has been intensively investigated; the regulatory mechanism underlying P-gp transport activity remains obscure. Herein, we reported that Rack1 and tyrosine kinase Src confer drug resistance through modulating the transport function of P-gp without altering its protein level. We provide evidences that Rack1 and Src regulate P-gp activity by modulating caveolin-1 (Cav1) phosphorylation. Importantly, Rack1 acts as a signaling hub and mediates Src binding to P-gp, thereby facilitating the phosphorylation of Cav1 by Src and abolishing the inhibitory effect of Cav1 on P-gp. Taken together, our results demonstrate the pivotal roles of Rack1 and Src in modulating P-gp activity in drug-resistant cells. Our findings also provide novel insights into the mechanism regulating P-gp transport activity. Rack1 may represent a new target for the development of effective therapies for reversing drug resistance.