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-Escin 通过 ROS 依赖性 HIF-1α/TGF-β/MMP 在 A549 细胞中减轻氯化钴诱导的缺氧介导的细胞凋亡抵抗和侵袭。


缺氧会导致多种病理生理状况，包括肥胖、心血管疾病和癌症。在癌症中，缺氧是一种突出的现象，与肿瘤进展、转移和引发癌症患者对治疗的抵抗相关，这与主要效应器缺氧诱导因子 1 α (HIF-1α) 的稳定发挥作用。因此，针对癌症缺氧反应的治疗是提高治疗效果的潜在方法。在本研究中，我们评估了 β-七叶皂苷 (β-Es) 对缺氧诱导的人非小细胞肺癌细胞凋亡和转移抵抗力的影响。 MTT分析显示，β-Es处理降低了氯化钴诱导的缺氧下A549细胞的活力。通过蛋白质印迹分析凋亡蛋白，结果显示与常氧相比，用 β-Es 处理的癌细胞在缺氧条件下诱导细胞死亡作为蛋白质。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，并稳定转录因子 HIF-1α，从而导致癌症转移。这一观点得到了迁移、侵袭和粘附测定的支持。此外，缺氧增加了转化生长因子-β的表达，并且β-Es处理以及N-乙酰半胱氨酸（NAC）预处理抑制了基质金属蛋白酶的活化。因此，我们证明 HIF-1α、转化生长因子-β 和基质金属蛋白酶的同时激活参与缺氧诱导的转移，并且 β-Es 通过抑制活性氧来防止 A549 细胞转移。