The DOI matches its Crossref record; 13 of the 13 references it cites were found in a registry or an index.
Metformin activates AMPK/SIRT1/NF-κB pathway and induces mitochondrial dysfunction to drive caspase3/GSDME-mediated cancer cell pyroptosis
Open accessAbstract
Pyroptosis is a form of programmed cell death initiated by inflammasomes and is critical for immunity. SIRT1, a NAD+-dependent deacetylase, plays multiple roles in inflammatory response and immunity. Metformin can activate SIRT1 to participate in different biological processes and exert its anticancer effects. However, the mechanism by which metformin activates SIRT1 to drive cancer cell pyroptosis has not been reported. In this study, we treated cancer cells with metformin for diverse periods of time (0-24 h) and found that cell viability was decreased obviously. Interestingly, pyroptosis occurred when cancer cells were treated with metformin for the indicated time (4, 8 and 12 h), which was elucidated by the cell swelling and bubbles blowing in the membrane. Metformin also increased the release of lactate dehydrogenase (LDH, an indication of pyroptotic cell cytotoxicity) remarkably. The underlying mechanisms were that metformin enhanced AMPK/SIRT1 pathway and further increased NF-κB p65 expression to stimulate Bax activation and cytochrome c release, triggering caspase3 cleavage of GSDME, which is a characteristic pyroptotic marker. Depletion of SIRT1 inhibited metformin-induced these protein expression, revealing that metformin promotes AMPK/SIRT1/NF-κB signaling to drive cancer cell pyroptosis. Meantime, metformin induced mitochondrial dysfunction to trigger activation of caspase3 and generation of GSDME-N. Moreover, mitochondrial dysfunction activated AMPK/SIRT1 pathway to cause pyroptotic death upon metformin treatment. This research firstly reveals that metformin as a sensitizer amplifies AMPK/SIRT1/NF-κB signaling to induce caspase3/GSDME-mediated cancer cell pyroptosis. Induction of cellular pyroptosis by metformin is considered as a novel therapeutic option against various cancers.
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AMPK regulates energy expenditure by modulating NAD+ metabolism and SIRT1 activity
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Inflammasome-activated gasdermin D causes pyroptosis by forming membrane pores
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Chemotherapy drugs induce pyroptosis through caspase-3 cleavage of a gasdermin
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Pyroptosis: Gasdermin-Mediated Programmed Necrotic Cell Death
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Pore-forming activity and structural autoinhibition of the gasdermin family
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Non-canonical inflammasome activation targets caspase-11
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“Stimulation of the mitochondrial apoptotic pathway by Bax leads to caspase3 activation to cleave GSDME in GSDME-expressing 293 T cells [15].”
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Metadata
- Authors
- Zheng, Z., Bian, Y., Zhang, Y., Ren, G., & Li, G.
- Venue
- Cell Cycle
- Publisher
- Informa UK Limited
- Published
- 2020-04-14
- Volume
- 19
- Issue
- 10
- Pages
- 1089-1104
- ISSN
- 1538-4101 (ISSN-L)
- 1551-4005
- OpenAlex
- W3015590570
- Cited by
- 245
- References
- 13
- FWCI
- 7.19
- Type
- journal article
- Language
- en
- Open access
- bronze
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- Zheng, Z., Bian, Y., Zhang, Y., Ren, G., & Li, G. (2020). Metformin activates AMPK/SIRT1/NF-κB pathway and induces mitochondrial dysfunction to drive caspase3/GSDME-mediated cancer cell pyroptosis. Cell Cycle. https://doi.org/10.1080/15384101.2020.1743911
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