Taxol-induced unfolded protein response activation in breast cancer cells exposed to hypoxia: ATF4 activation regulates autophagy and inhibits apoptosis
Taxol-induced unfolded protein response activation in breast cancer cells exposed to hypoxia: ATF4 activation regulates autophagy and inhibits apoptosis
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DOI：
10.1016/j.biocel.2015.02.010
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发表时间：
2015-05-01
影响因子：
4
通讯作者：
Michiels, Carine
中科院分区：
文献类型：
--
作者：
Notte, Annick;Rebucci, Magali;Michiels, Carine
了解负责抵抗化疗诱导的细胞死亡的机制仍然是非常感兴趣的，因为癌症患者的数量增加，复发是常见的。事实上，已知缺氧区域的发展以及UPR（未折叠蛋白反应）活化促进癌细胞对应激肿瘤微环境的适应性反应和对抗癌疗法的抗性。因此，在MDA MB-231和T47 D乳腺癌细胞中研究了UPR结合低氧对紫杉醇暴露期间自噬和凋亡激活的影响。结果表明，紫杉醇能迅速诱导UPR活化，缺氧对紫杉醇诱导的UPR活化的调节作用因UPR通路的不同而不同（PERK、ATF 6和IRElot）。研究了这些信号通路可能参与自噬或响应紫杉醇暴露的细胞凋亡调节。然而，虽然这三种ER应激传感器的激活与自噬或凋亡调节之间没有联系，但结果表明，ATF 4的激活（独立于UPR激活）参与了紫杉醇诱导的自噬完成。此外，证明了导致癌细胞适应和对紫杉醇诱导的细胞死亡的抗性的ATF 4依赖性机制。最后，我们的研究结果表明，与缺氧诱导的基因，ATF 4的表达，可作为人类乳腺癌患者预后不良的生物标志物支持的结论，即ATF 4可能发挥重要作用，在适应和耐药的乳腺癌细胞化疗缺氧肿瘤。(C)2015爱思唯尔有限公司版权所有。
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.