Selective Reversible Inhibition of Autophagy in Hypoxic Breast Cancer Cells Promotes Pulmonary Metastasis.
Selective Reversible Inhibition of Autophagy in Hypoxic Breast Cancer Cells Promotes Pulmonary Metastasis.
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DOI：
10.1158/0008-5472.can-15-3458
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发表时间：
2017-02-01
期刊：
影响因子：
11.2
通讯作者：
Wang HG
中科院分区：
文献类型：
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作者：
Dower CM;Bhat N;Wang EW;Wang HG
自噬影响癌细胞对营养剥夺和缺氧应激的反应，这是肿瘤微环境（TME）的两个标志。在这项研究中，我们探索了自噬对乳腺癌细胞病理生理的影响，利用一种新的缺氧依赖、可逆的显性负性策略在细胞水平上调节TME内的自噬。在MDA-MB-231异种移植小鼠模型中，通过缺氧诱导激酶死亡的unc-51样自噬激活激酶（ULK1）突变体K46N的表达抑制自噬增加了肺转移。与这种效应一致，表达ULK1或ATG4b的显性阴性突变体或ULK1靶向shRNA促进了细胞在体外的迁移。功能蛋白质组学和转录组学分析显示，缺氧调节的自噬缺失通过诱导纤维连接蛋白整合素信号轴促进转移。事实上，ULK1功能的丧失增加了缺氧TME中纤维连接蛋白的沉积。总之，我们的研究结果表明，缺氧调节的自噬通过防止肿瘤纤维化来抑制乳腺癌的转移。这些结果也提示在开发基于自噬的癌症治疗策略时需要注意。
Autophagy influences how cancer cells respond to nutrient deprivation and hypoxic stress, two hallmarks of the tumor microenvironment (TME). In this study, we explored the impact of autophagy on the pathophysiology of breast cancer cells, using a novel hypoxia-dependent, reversible dominant negative strategy to regulate autophagy at the cellular level within the TME. Suppression of autophagy via hypoxia-induced expression of the kinase-dead unc-51 like autophagy activating kinase (ULK1) mutant K46N increased lung metastases in MDA-MB-231 xenograft mouse models. Consistent with this effect, expressing a dominant-negative mutant of ULK1 or ATG4b or a ULK1-targeting shRNA facilitated cell migration in vitro. Functional proteomic and transcriptome analysis revealed that loss of hypoxia-regulated autophagy promotes metastasis via induction of the fibronectin integrin signaling axis. Indeed, loss of ULK1 function increased fibronectin deposition in the hypoxic TME. Together, our results indicated that hypoxia-regulated autophagy suppresses metastasis in breast cancer by preventing tumor fibrosis. These results also suggest cautions in the development of autophagy-based strategies for cancer treatment.