二甲双胍逆转低氧诱导的胰腺癌细胞铁死亡抵抗及潜在的作用机制

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Abstract Objective: To investigate whether metformin can reverse hypoxiainduced resistance to ferroptosis in pancreatic cancer cells and to further clarify its mechanism. Methods: Human pancreatic cancer cells Patu8988 were cultured under normoxia and hypoxia conditions for different time (0, 12, 24 or 48 h). CCK8 assay was used to detect the cell viability and Western blotting was used to detect the protein expression of hypoxia-inducible factor 1α (HIF1α); CCK8 assay was used to detect the cell viability of Patu8988 cells treated with different concentrations of ferroptosis inducer Erastin in normoxia and hypoxia conditions; the hypoxiacultured Patu8988 cells were divided into the following four treatment groups: control group, metformin group, Erastin group, metformin+Erastin group. CCK8 assay was used to detect the cell viability, Western blotting was used to detect the protein expression level of glutathione peroxidase 4 (GPX4). Patu8988 cells in hypoxia culture were treated with different concentrations of metformin, and Western blotting was used to detect the protein expression levels of AMPactivated protein kinase (AMPK), mammalian target of rapamycin (mTOR), HIF-1α and other proteins. Results: Compared with the normoxia group, hypoxia inhibited the cell viability in a timedependence manner, and the difference between two groups was the most significant at 48 h (P<0.05). When the concentration of Erastin was 10 μmol/L, the cell viability of the hypoxia group was significantly lower than that of the normoxia group (P<0.05), and 10 μmol/L was the best experimental concentration. Compared with the group treated alone in hypoxia condition, the combined treatment could significantly inhibit the cell viability and reduce the protein expression level of GPX4 (both P<0.05). By activating AMPK, inhibiting mTOR phosphorylation, metformin negatively regulated HIF-1α protein expression level (both P<0.05). Conclusion: Metformin could reduce the accumulation of HIF-1α through the AMPK-mTOR axis, thus reversing hypoxia-induced resistance to ferroptosis in pancreatic cancer cells.

Received: 10 January 2020

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http://zzs.ujs.edu.cn/xbyxb/EN/ OR http://zzs.ujs.edu.cn/xbyxb/EN/Y2020/V30/I02/125

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