Integrin signaling inhibits paclitaxel-induced apoptosis in breast cancer cells
Integrin signaling inhibits paclitaxel-induced apoptosis in breast cancer cells
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DOI：
10.1038/sj.onc.1204554
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发表时间：
2001-08-16
期刊：
影响因子：
8
通讯作者：
Vuori, K
中科院分区：
文献类型：
--
作者：
Aoudjit, F;Vuori, K
固有或获得性耐药是化疗中的主要问题之一。癌细胞生存和逃避化疗药物细胞毒性作用的机制基本上是未知的。在本研究中，我们证明了在MDA-MB-231和MDA-MB-435乳腺癌细胞中，β 1整合素通过其细胞外基质配体连接可显著抑制紫杉醇和长春新碱两种微管定向化疗药物诱导的凋亡，这两种药物广泛用于乳腺癌的治疗。我们发现β 1整合素信号通过抑制线粒体对药物治疗的细胞色素c的释放来抑制药物诱导的细胞凋亡。此外，整合素介导的药物诱导凋亡保护和细胞色素c释放抑制依赖于PI 3-激酶/Akt通路的激活。我们的研究结果确定β 1整合素信号是药物诱导乳腺癌细胞凋亡的重要生存途径，并提示该途径的激活可能有助于耐药性的产生。
Inherent or acquired drug resistance is one of the major problems in chemotherapy. The mechanisms by which cancer cells survive and escape the cytotoxic effects of chemotherapeutic agents are essentially unknown. In the present study, we demonstrate that in the MDA-MB-231 and MDA-MB-435 breast cancer cells, ligation of beta1 integrins by their extracellular matrix ligands inhibits significantly apoptosis induced by paclitaxel and vincristine, two microtubule-directed chemotherapeutic agents that are widely used in the therapy of breast cancer. We show that beta1 integrin signaling inhibits drug-induced apoptosis by inhibiting the release of cytochrome c from the mitochondria in response to drug treatment. Further, integrin-mediated protection from drug-induced apoptosis and inhibition of cytochrome c release are dependent on the activation of the PI 3-kinase/Akt pathway. Our results identify beta1 integrin signaling as an important survival pathway in drug-induced apoptosis in breast cancer cells and suggest that activation of this pathway may contribute to the generation of drug resistance.