期刊
CANCER LETTERS
卷 450, 期 -, 页码 22-31出版社
ELSEVIER IRELAND LTD
DOI: 10.1016/j.canlet.2019.02.014
关键词
Metformin; Pyroptosis; GSDMD; miR-497; Chemotherapy resistance
类别
资金
- National Natural Science Foundation of China [81572876, 81773087, 81071736, 30973508]
- Li Ka Shing Foundation
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.
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