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首页> 外文期刊>The international journal of biochemistry and cell biology >Taxol-induced unfolded protein response activation in breast cancer cells exposed to hypoxia: ATF4 activation regulates autophagy and inhibits apoptosis
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Taxol-induced unfolded protein response activation in breast cancer cells exposed to hypoxia: ATF4 activation regulates autophagy and inhibits apoptosis

机译：紫杉醇诱导的缺氧乳腺癌细胞中未折叠的蛋白反应激活：ATF4激活调节自噬并抑制细胞凋亡

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Understanding the mechanisms responsible for the resistance against chemotherapy-induced cell death is still of great interest since the number of patients with cancer increases and relapse is commonly observed. Indeed, the development of hypoxic regions as well as UPR (unfolded protein response) activation is known to promote cancer cell adaptive responses to the stressful tumor microenvironment and resistance against anticancer therapies. Therefore, the impact of UPR combined to hypoxia on autophagy and apoptosis activation during taxol exposure was investigated in MDA MB-231 and T47D breast cancer cells. The results showed that taxol rapidly induced UPR activation and that hypoxia modulated taxolinduced UPR activation differently according to the different UPR pathways (PERK, ATF6, and IRElot.). The putative involvement of these signaling pathways in autophagy or in apoptosis regulation in response to taxol exposure was investigated. However, while no link between the activation of these three ER stress sensors and autophagy or apoptosis regulation could be evidenced, results showed that ATF4 activation, which occurs independently of UPR activation, was involved in taxol-induced autophagy completion. In addition, an ATF4-dependent mechanism leading to cancer cell adaptation and resistance against taxolinduced cell death was evidenced. Finally, our results demonstrate that expression of ATF4, in association with hypoxia-induced genes, can be used as a biomarker of a poor prognosis for human breast cancer patients supporting the conclusion that ATF4 might play an important role in adaptation and resistance of breast cancer cells to chemotherapy in hypoxic tumors. (C) 2015 Elsevier Ltd. All rights reserved.
机译：由于通常会观察到癌症患者的数量增加和复发，因此了解引起对化学疗法诱导的细胞死亡的抗性的机制仍然非常重要。实际上，已知缺氧区域的发展以及UPR（未折叠的蛋白应答）激活可促进癌细胞对应激性肿瘤微环境的适应性反应以及对抗癌疗法的抵抗力。因此，在MDA MB-231和T47D乳腺癌细胞中研究了UPR联合缺氧对紫杉醇暴露过程中自噬和细胞凋亡激活的影响。结果表明，紫杉醇根据不同的UPR途径（PERK，ATF6和IRElot）快速诱导UPR活化，而低氧调节的紫杉醇诱导的UPR活化也不同。研究了这些信号通路在涉及紫杉醇暴露的自噬或凋亡调控中的假定参与。然而，虽然这三个内质网应激传感器的激活与自噬或细胞凋亡调节之间没有联系，但结果表明，独立于UPR激活而发生的ATF4激活与紫杉醇诱导的自噬完成有关。另外，已证实导致癌细胞适应和抗紫杉醇诱导的细胞死亡的ATF4依赖性机制。最后，我们的结果表明，ATF4的表达与缺氧诱导的基因有关，可作为人类乳腺癌患者预后不良的生物标志物，支持以下结论：ATF4可能在乳腺癌的适应性和耐药性中起重要作用细胞在缺氧肿瘤中进行化学疗法。 （C）2015 Elsevier Ltd.保留所有权利。

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