Collagen/β1 integrin signaling up-regulates the ABCC1/MRP-1 transporter in an ERK/MAPK-dependent manner.
Collagen/β1 integrin signaling up-regulates the ABCC1/MRP-1 transporter in an ERK/MAPK-dependent manner.
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DOI：
10.1091/mbc.e12-02-0132
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发表时间：
2012-09
影响因子：
3.3
通讯作者：
Aoudjit F
中科院分区：
文献类型：
--
作者：
El Azreq MA;Naci D;Aoudjit F
胶原/β1整合素/细胞外信号调节激酶信号通路上调ABCC 1转运蛋白的表达和功能。这表明它的激活可能是癌症耐药性的一个重要途径。β1整合素调节癌细胞化疗耐药性的机制仍知之甚少。在这项研究中，我们报告了胶原/β1整合素信号通过上调ATP结合盒C1（ABCC 1）转运蛋白（也称为多药耐药相关蛋白1）的表达和功能来抑制阿霉素诱导的Jurkat和HSB 2白血病T细胞凋亡。我们发现，胶原蛋白，而不是纤连蛋白减少细胞内阿霉素含量和上调ABCC 1的表达水平。抑制和敲低研究表明，上调ABCC 1是必要的胶原介导的细胞内阿霉素含量的减少和胶原介导的抑制阿霉素诱导的细胞凋亡。我们还表明，细胞外信号调节激酶（ERK）/丝裂原活化蛋白激酶信号通路的激活参与胶原诱导的细胞内阿霉素积累的减少，胶原诱导的ABCC 1表达水平的上调，和胶原介导的细胞存活。最后，胶原介导的ABCC 1表达和功能的上调也需要肌动蛋白聚合。综上所述，我们的结果首次表明胶原/β1整合素/ERK信号转导上调ABCC 1的表达和功能，并表明其活化可能代表癌症化疗耐药性的重要途径。因此，同时靶向胶原蛋白/β1整联蛋白和ABCC 1可能比单独靶向每种途径更有效地预防耐药性。
Collagen/β1 integrin/extracellular signal-regulated kinase signaling up-regulates the expression and function of ABCC1 transporter. This suggests that its activation could represent an important pathway in cancer chemoresistance. The mechanisms by which β1 integrins regulate chemoresistance of cancer cells are still poorly understood. In this study, we report that collagen/β1 integrin signaling inhibits doxorubicin-induced apoptosis of Jurkat and HSB2 leukemic T-cells by up-regulating the expression and function of the ATP-binding cassette C 1 (ABCC1) transporter, also known as multidrug resistance–associated protein 1. We find that collagen but not fibronectin reduces intracellular doxorubicin content and up-regulates the expression levels of ABCC1. Inhibition and knockdown studies show that up-regulation of ABCC1 is necessary for collagen-mediated reduction of intracellular doxorubicin content and collagen-mediated inhibition of doxorubicin-induced apoptosis. We also demonstrate that activation of the extracellular signal-regulated kinase (ERK)/mitogen-activated protein kinase signaling pathway is involved in collagen-induced reduction of intracellular doxorubicin accumulation, collagen-induced up-regulation of ABCC1 expression levels, and collagen-mediated cell survival. Finally, collagen-mediated up-regulation of ABCC1 expression and function also requires actin polymerization. Taken together, our results indicate for the first time that collagen/β1 integrin/ERK signaling up-regulates the expression and function of ABCC1 and suggest that its activation could represent an important pathway in cancer chemoresistance. Thus simultaneous targeting of collagen/β1 integrin and ABCC1 may be more efficient in preventing drug resistance than targeting each pathway alone.