Hypoxia is contributed in various pathophysiological conditions including obesity, cardiovascular diseases, and cancer. In cancer, hypoxia is a salient phenomenon and has been correlated with tumor progression, metastasis, and provoke resistance to therapies in cancer patients, which exert with stabilization of main effector, hypoxia inducible factor-1 alpha (HIF-1α). Therefore, therapeutic targeting of hypoxic responses in cancer is the potential approach to improve the better treatment efficacy. In the present study, we evaluated the effect of β-Escin (β-Es) on hypoxia-induced resistance to apoptosis and metastasis in human non–small-cell lung cancer cells. The MTT assay revealed that β-Es treatment decreased the A549 cells viability under cobalt chloride-induced hypoxia. Apoptotic proteins were analyzed by western blot that showed cancer cells treated with β-Es induced cell death in hypoxia condition as proteins compared with normoxia. Moreover, we observed that cobalt chloride induced hypoxia through the generation of intracellular reactive oxygen species and stabilized the transcriptional factor HIF-1α, which leads to cancer metastasis. This notion was supported by the migration, invasion, and adhesion assays. Furthermore, hypoxia increased the expression of transforming growth factor-β, and the activation of matrix metalloproteinases were suppressed by the treatment of β-Es as well as pretreatment with N-acetylcysteine (NAC). Therefore, we demonstrate that a concurrent activation of HIF-1α, transforming growth factor-β, and matrix metalloproteinases participate in hypoxia-induced metastasis and that β-Es prevent A549 cells metastasis by inhibition of reactive oxygen species.

中文翻译：

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β-七叶皂苷通过ROS依赖性HIF-1α/TGF-β/ MMP减轻A549细胞中氯化钴诱导的缺氧介导的凋亡抗性和侵袭。

缺氧是导致肥胖，心血管疾病和癌症等各种病理生理状况的原因。在癌症中，缺氧是一个显着现象，并且与癌症患者的肿瘤进展，转移和激起的对治疗的耐药性相关，这与主要效应子缺氧诱导因子-1α（HIF-1α）的稳定发挥作用。因此，针对癌症中缺氧反应的治疗靶点是改善更好治疗效果的潜在途径。在本研究中，我们评估了β-Escin（β-Es）对缺氧诱导的人非小细胞肺癌细胞凋亡和转移耐药性的影响。MTT分析显示，在氯化钴诱导的缺氧条件下，β-Es处理降低了A549细胞的活力。通过蛋白质印迹分析凋亡蛋白，结果显示，与正常氧相比，用β-Es处理的癌细胞在缺氧条件下诱导细胞死亡。此外，我们观察到氯化钴通过细胞内活性氧的产生诱导缺氧并稳定了转录因子HIF-1α，从而导致癌症转移。迁移，入侵和粘附分析支持了这一观点。此外，缺氧增加了转化生长因子-β的表达，并且通过β-E的处理以及N-乙酰半胱氨酸（NAC）的预处理抑制了基质金属蛋白酶的活化。因此，我们证明了HIF-1α的同时激活，转化生长因子-β，