Rack1 mediates tyrosine phosphorylation of Anxa2 by Src and promotes invasion and metastasis in drug-resistant breast cancer cells
Rack1 mediates tyrosine phosphorylation of Anxa2 by Src and promotes invasion and metastasis in drug-resistant breast cancer cells
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Rack1通过Src介导Anxa2酪氨酸磷酸化并促进耐药乳腺癌细胞的侵袭和转移
DOI：
10.1186/s13058-019-1147-7
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发表时间：
2019-05-22
影响因子：
7.4
通讯作者：
Zhang，Fei
中科院分区：
文献类型：
--
作者：
Fan，Yanling;Si，Weiyao;Zhang，Fei
背景获得耐药总是与肿瘤细胞的高度侵袭性表型相关。近年来的研究发现，膜联蛋白A2（Annexin A2，Anxa 2）是一种连接耐药和肿瘤转移的关键蛋白。癌组织中高水平的Anxa 2与高度侵袭性表型相关。Anxa 2表达增加似乎在许多耐药癌细胞中是特异性的。Anxa 2的功能活性由Tyr 23位点的酪氨酸磷酸化调节。然而，Anxa 2酪氨酸磷酸化调节的精确分子机制以及磷酸化是否是增强耐药细胞侵袭表型所必需的仍然是未知的。采用小鼠体内转移模型，研究Rack 1和Src对Anxa 2酪氨酸磷酸化的影响以及对乳腺癌耐药细胞侵袭转移能力的影响。Rack 1，Src，和Anxa 2在耐药细胞之间的相互作用进行了验证，通过免疫共沉淀assay.ResultsWe证明，Anxa 2 Tyr 23磷酸化是必要的多药耐药乳腺癌的侵袭和转移。Rack 1通过调节Anxa 2磷酸化对耐药乳腺癌细胞的侵袭和转移潜力是必需的。我们提供的证据表明，Rack 1作为一个信号枢纽，介导Src和Anxa 2之间的相互作用，从而促进Anxa 2磷酸化Src kinase.ConclusionsOur研究结果表明，Rack 1/Src/Anxa 2复合物的聚合点作用的耐药性和癌症的侵袭性之间的串扰。Anxa 2和Rack 1/Src之间的相互作用是乳腺癌细胞耐药性和侵袭/转移潜力之间的联系。因此，我们的研究结果为耐药性和癌症侵袭性之间的功能联系机制提供了新的见解。
BackgroundAcquirement of resistance is always associated with a highly aggressive phenotype of tumor cells. Recent studies have revealed that Annexin A2 (Anxa2) is a key protein that links drug resistance and cancer metastasis. A high level of Anxa2 in cancer tissues is correlated to a highly aggressive phenotype. Increased Anxa2 expression appears to be specific in many drug-resistant cancer cells. The functional activity of Anxa2 is regulated by tyrosine phosphorylation at the Tyr23 site. Nevertheless, the accurate molecular mechanisms underlying the regulation of Anxa2 tyrosine phosphorylation and whether phosphorylation is necessary for the enhanced invasive phenotype of drug-resistant cells remain unknown.MethodsSmall interfering RNAs, small molecule inhibitors, overexpression, loss of function or gain of function, rescue experiments, Western blot, wound healing assays, transwell assays, and in vivo metastasis mice models were used to investigate the functional effects of Rack1 and Src on the tyrosine phosphorylation of Anxa2 and the invasion and metastatic potential of drug-resistant breast cancer cells. The interaction among Rack1, Src, and Anxa2 in drug-resistant cells was verified by co-immunoprecipitation assay.ResultsWe demonstrated that Anxa2 Tyr23 phosphorylation is necessary for multidrug-resistant breast cancer invasion and metastasis. Rack1 is required for the invasive and metastatic potential of drug-resistant breast cancer cells through modulating Anxa2 phosphorylation. We provided evidence that Rack1 acts as a signal hub and mediates the interaction between Src and Anxa2, thereby facilitating Anxa2 phosphorylation by Src kinase.ConclusionsOur findings suggest a convergence point role of Rack1/Src/Anxa2 complex in the crosstalk between drug resistance and cancer aggressiveness. The interaction between Anxa2 and Rack1/Src is responsible for the association between drug resistance and invasive/metastatic potential in breast cancer cells. Thus, our findings provide novel insights on the mechanism underlying the functional linkage between drug resistance and cancer aggressiveness.