Microvesicle removal of anticancer drugs contributes to drug resistance in human pancreatic cancer cells.
Microvesicle removal of anticancer drugs contributes to drug resistance in human pancreatic cancer cells.
复制标题
DOI：
10.18632/oncotarget.10395
复制
发表时间：
2016-08-02
期刊：
影响因子：
--
通讯作者：
Mousa SA
中科院分区：
文献类型：
--
作者：
Muralidharan-Chari V;Kohan HG;Asimakopoulos AG;Sudha T;Sell S;Kannan K;Boroujerdi M;Davis PJ;Mousa SA
胰腺癌患者的高死亡率部分是由于对化疗的耐药性。我们描述了人类胰腺癌细胞通过一种新机制获得耐药性，其中它们通过微囊泡（mv）从微环境中排出和去除化疗药物。使用对吉西他滨（GEM）表现出不同敏感性的人类胰腺癌细胞，我们发现GEM暴露会触发癌细胞释放mv，其数量与该细胞系对GEM的敏感性相关。在体外和体内实验中，抑制mv释放使细胞对GEM治疗增敏，证实了mv释放在GEM耐药胰腺癌细胞获得耐药性中的重要性。从机制上讲，mv去除内化到细胞中的药物和微环境。本文测试的耐药和药物敏感胰腺癌细胞系之间的差异是基于mv上存在的内流/外排蛋白的可变含量来解释的，这直接决定了mv捕获GEM或允许GEM流回微环境的能力。
High mortality in pancreatic cancer patients is partly due to resistance to chemotherapy. We describe that human pancreatic cancer cells acquire drug resistance by a novel mechanism in which they expel and remove chemotherapeutic drugs from the microenvironment via microvesicles (MVs). Using human pancreatic cancer cells that exhibit varied sensitivity to gemcitabine (GEM), we show that GEM exposure triggers the cancer cells to release MVs in an amount that correlates with that cell line's sensitivity to GEM. The importance of MV-release in gaining drug resistance in GEM-resistant pancreatic cancer cells was confirmed when the inhibition of MV-release sensitized the cells to GEM treatment, both in vitro and in vivo. Mechanistically, MVs remove drugs that are internalized into the cells and that are in the microenvironment. The differences between the drug-resistant and drug-sensitive pancreatic cancer cell lines tested here are explained based on the variable content of influx/efflux proteins present on MVs, which directly dictates the ability of MVs either to trap GEM or to allow GEM to flow back to the microenvironment.