Implications of increased tissue transglutaminase (TG2) expression in drug-resistant breast cancer (MCF-7) cells
Implications of increased tissue transglutaminase (TG2) expression in drug-resistant breast cancer (MCF-7) cells
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DOI：
10.1038/sj.onc.1209324
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发表时间：
2006-05-18
期刊：
影响因子：
8
通讯作者：
Mehta, K.
中科院分区：
文献类型：
--
作者：
Herman, J. F.;Mangala, L. S.;Mehta, K.
对化疗药物的耐药性的发展是成功治疗乳腺癌的主要障碍。阻断或克服这种阻力的方法是人们激烈研究的对象。我们之前已经证明，对化疗药物产生耐药性的癌细胞或从转移性肿瘤部位分离出来的癌细胞具有高水平的钙依赖性蛋白交联酶，组织转谷氨酰胺酶（TG2），但TG2与耐药性之间没有直接联系。由于TG2可以与整合素家族蛋白的ss成员结合，我们假设TG2通过激活这些细胞表面的整合素来促进细胞存活信号通路。为了验证这一假设，我们研究了TG2在耐药MCF-7乳腺癌细胞中的表达及其与各种整合素的相互作用。TG2与耐药MCF-7 （MCF-7/Dox和MCF-7/RT）细胞表面的ss1和ss5整合素密切相关。表达tg2的耐药MCF-7细胞在纤维连接蛋白（Fn）包被的表面上孵育，强烈激活了局灶黏附激酶，这一事件导致几个下游信号通路的激活，反过来，可以赋予癌细胞抗凋亡表型。通过小干扰RNA （siRNA）方法进一步分析TG2在fn介导的细胞附着、细胞生长和细胞存活功能中的作用。在耐药MCF-7细胞中，sirna抑制fn介导的细胞附着和细胞存活功能对TG2的抑制我们得出结论，TG2在乳腺癌细胞中的表达通过促进整合素和Fn之间的相互作用，促进了耐药表型的发展。
The development of resistance to chemotherapeutic drugs is a major obstacle to the successful treatment of breast cancer. Ways to block or overcome this resistance are objects of intense research. We have previously shown that cancer cells selected for resistance against chemotherapeutic drugs or isolated from metastatic tumor sites have high levels of a calcium-dependent protein crosslinking enzyme, tissue transglutaminase (TG2) but no direct link between TG2 and resistance was established. As TG2 can associate with the ss members of the integrin family of proteins, we hypothesized that TG2 promotes cell survival signaling pathways by activating integrins on the surface of these cells. To test this hypothesis, we studied the expression of TG2 and its interaction with various integrins in drug-resistant MCF-7 breast cancer cells. TG2 closely associated with ss 1 and ss 5 integrins on the surface of drug-resistant MCF-7 (MCF-7/Dox and MCF-7/RT) cells. The incubation of TG2-expressing drug-resistant MCF-7 cells on fibronectin(Fn)-coated surfaces strongly activated focal adhesion kinase, an event that leads to the activation of several downstream signaling pathways and, in turn, can confer apoptosis-resistant phenotype to cancer cells. The role of TG2 in Fn-mediated cell attachment, cell growth, and cell survival functions was further analysed by small interfering RNA ( siRNA) approach. Inhibition of TG2 by siRNA-inhibited Fn-mediated cell attachment and cell survival functions in drug-resistant MCF-7 cells. We conclude that the expression of TG2 in breast cancer cells contributes to the development of the drug-resistance phenotype by promoting interaction between integrins and Fn.