Metformin induces human esophageal carcinoma cell pyroptosis by targeting the miR-497/PELP1 axis
Metformin induces human esophageal carcinoma cell pyroptosis by targeting the miR-497/PELP1 axis
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二甲双胍通过靶向miR-497/PELP1轴诱导人食管癌细胞焦亡
DOI：
10.1016/j.canlet.2019.02.014
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发表时间：
2019-01-01
期刊：
影响因子：
9.7
通讯作者：
Zhang, Hao
中科院分区：
文献类型：
--
作者：
Wang, Lu;Li, Kai;Zhang, Hao
细胞凋亡的逃避是化疗和放疗抵抗发展的主要因素。因此，非凋亡程序性细胞死亡（PCD）的激活可能是一种有效的替代抗凋亡的癌症。在这项研究中，我们在体外和体内证明了二甲双胍可以诱导食管鳞状细胞癌（ESCC）（一种通常已知的化学难治性癌症）中的焦亡（一种非凋亡PCD），尤其是在晚期。富含脯氨酸、谷氨酸和亮氨酸的蛋白-1（PELP 1）是一种支架癌基因，在晚期ESCC中PELP 1的上调与癌症进展和患者结局高度相关。有趣的是，二甲双胍治疗导致gasdermin D（GSDMD）介导的焦亡，其通过PELP 1的强制表达而消除。二甲双胍通过靶向miR-497/PELP 1轴诱导食管鳞癌细胞凋亡。我们的研究结果表明，二甲双胍和任何其他pyroptosis诱导剂可以作为化疗和放疗难治性ESCC或其他癌症共享相同的pyroptosis机制的替代治疗。
Evasion of apoptosis is a major contributing factor to the development of chemo- and radiotherapy resistance. Therefore, activation of non-apoptotic programmed cell death (PCD) could be an effective alternative against apoptosis-resistant cancers. In this study, we demonstrated in vitro and in vivo that metformin can induce pyroptosis, a non-apoptotic PCD, in esophageal squamous cell carcinoma (ESCC), a commonly known chemo-refractory cancer, especially at its advanced stages. Proline-, glutamic acid- and leucine-rich protein-1 (PELP1) is a scaffolding oncogene and upregulated PELP1 in advanced stages of ESCC is highly associated with cancer progression and patient outcomes. Intriguingly, metformin treatment leads to gasdermin D (GSDMD)-mediated pyroptosis, which is abrogated by forced expression of PELP1. Mechanistically, metformin induces pyroptosis of ESCC by targeting miR-497/PELP1 axis. Our findings suggest that metformin and any other pyroptosis-inducing reagents could serve as alternative treatments for chemo- and radiotherapy refractory ESCC or other cancers sharing the same pyroptosis mechanisms.