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Metformin activates AMPK/SIRT1/NF-κB pathway and induces mitochondrial dysfunction to drive caspase3/GSDME-mediated

Zhaodi Zheng1, Yan Bian1, Yang Zhang1

  • 1Shandong Provincial Key Laboratory of Animal Resistant, School of Life Sciences, Shandong Normal University, Jinan, China.

Cell Cycle (Georgetown, Tex.)
|April 15, 2020
PubMed

Insights

Metformin triggers cancer cell death through pyroptosis by activating the AMPK/SIRT1/NF-κB pathway. This study reveals metformin

Area of Science:

  • Cellular Biology
  • Immunology
  • Oncology

Background:

  • Pyroptosis is a critical inflammasome-mediated programmed cell death pathway involved in immunity.
  • Sirtuin 1 (SIRT1) is a NAD+-dependent deacetylase influencing inflammation and immunity.
  • Metformin activates SIRT1 and has demonstrated anticancer effects, but its role in cancer cell pyroptosis is unclear.

Purpose of the Study:

  • To elucidate the mechanism by which metformin activates SIRT1 to induce pyroptosis in cancer cells.
  • To investigate the role of the AMPK/SIRT1/NF-κB signaling pathway in metformin-induced pyroptosis.
  • To explore metformin's potential as a sensitizer for cancer therapy via pyroptosis induction.

Main Methods:

  • Cancer cells were treated with metformin for varying durations (0-24 hours).
  • Pyroptosis was assessed by observing cell morphology (swelling, membrane blebbing) and measuring lactate dehydrogenase (LDH) release.
  • Key protein expressions (AMPK, SIRT1, NF-κB p65, Bax, cytochrome c, caspase3, GSDME) and mitochondrial function were analyzed.
  • SIRT1 depletion was used to confirm its role in the observed effects.

Main Results:

  • Metformin treatment significantly decreased cancer cell viability and induced pyroptosis.
  • Metformin enhanced the AMPK/SIRT1 pathway, leading to increased NF-κB p65 expression, Bax activation, and cytochrome c release.
  • Caspase3 cleavage of Gasdermin E (GSDME) was observed, a hallmark of pyroptosis, alongside metformin-induced mitochondrial dysfunction.
  • SIRT1 depletion abrogated metformin's effects on protein expression and pyroptosis induction.

Conclusions:

  • Metformin amplifies the AMPK/SIRT1/NF-κB signaling pathway to drive caspase3/GSDME-mediated pyroptosis in cancer cells.
  • Metformin induces mitochondrial dysfunction, which further activates the AMPK/SIRT1 pathway, leading to pyroptotic cell death.
  • Metformin acts as a sensitizer, offering a novel therapeutic strategy for cancer treatment by inducing pyroptosis.
Keywords:
AMPK/SIRT1/NF-κBMetformincaspase3/GSDMEmitochondrial dysfunctionpyroptosis

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