P-glycoprotein associates with Anxa2 and promotes invasion in multidrug resistant breast cancer cells
P-glycoprotein associates with Anxa2 and promotes invasion in multidrug resistant breast cancer cells
复制标题
P-糖蛋白与 Anxa2 结合并促进多药耐药乳腺癌细胞的侵袭
DOI：
10.1016/j.bcp.2013.11.003
复制
发表时间：
2014-01-15
影响因子：
5.8
通讯作者：
Niu, Ruifang
中科院分区：
文献类型：
--
作者：
Zhang, Fei;Zhang, Haichang;Niu, Ruifang
最近的一些研究表明，多药耐药（MDR）表型的获得与肿瘤细胞侵袭和转移的增加有关。p -糖蛋白（P-gp）是MDR表型产生的主要决定因素，据报道，在许多形式的恶性肿瘤中，p -糖蛋白与更具侵袭性的表型和不良预后相关。然而，对两者之间的联系仍缺乏清晰的认识。我们之前的研究表明，钙依赖性磷脂结合蛋白Anxa2与P-gp相互作用，有助于耐多药乳腺癌细胞的侵袭。在本研究中，我们发现浸润性乳腺癌组织中MDR1和Anxa2 mRNA的表达在癌症进展过程中呈强正相关。此外，暴露于阿霉素可显著增强乳腺癌细胞的运动性，并增加P-gp和Anxa2的水平。此外，使用选择性P-gp调节剂抑制P-gp活性可显著抑制MCF-7/ADR细胞的侵袭能力，而不影响P-gp与Anxa2之间的相互作用和共定位。然而，P-gp泵活性的抑制和MDR1表达的下调都破坏了阿霉素诱导的Anxa2磷酸化。有趣的是，P-gp进一步被证明与Src相互作用，Src是Anxa2上游的一种酪氨酸激酶。综上所述，我们的研究结果表明，P-gp可能通过调节Anxa2的酪氨酸磷酸化来促进耐多药乳腺癌细胞的侵袭。Anxa2和P-gp之间的相互作用可能，至少在一定程度上，是MDR和乳腺癌细胞侵袭潜力之间关联的原因。(C) 2013爱思唯尔公司版权所有。
Several recent studies have suggested that the acquisition of the multidrug resistance (MDR) phenotype is associated with elevated invasion and metastasis of tumor cells. P-glycoprotein (P-gp), the major determinant in the generation of the MDR phenotype, was reported to be correlated with a more aggressive phenotype and poor prognosis in many forms of malignancies. However, a clear understanding of the association is still lacking. We previously showed that Anxa2, a calcium-dependent phospholipid-binding protein, interacts with P-gp and contributes to the invasiveness of MDR breast cancer cells. In the present study, a strong positive correlation between MDR1 and Anxa2 mRNA expression in invasive breast cancer tissues during cancer progression was observed. In addition, exposure to adriamycin significantly enhanced motility in breast cancer cells and increased levels of P-gp and Anxa2. Moreover, inhibition of P-gp activity, using selective P-gp modulators, was found to significantly inhibit the invasive capacity of MCF-7/ADR cells without affecting the interaction and co-localization between P-gp and Anxa2. However, suppression of P-gp pump activity and knockdown of MDR1 expression both disrupted adriamycin-induced Anxa2 phosphorylation. Interestingly, P-gp was further demonstrated to interact with Src, a tyrosine kinase upstream of Anxa2. Taken together, our results indicate that P-gp may promote the invasion of MDR breast cancer cells by modulating the tyrosine phosphorylation of Anxa2. The interaction between Anxa2 and P-gp is possibly, at least in part, responsible for the association between MDR and invasive potential in breast cancer cells. (C) 2013 Elsevier Inc. All rights reserved.