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

Zheng, Zhaodi; Bian, Yan; Zhang, Yang; Ren, Guanghui; Li, Guorong

doi:10.1080/15384101.2020.1743911

Cited by 160 publications

(89 citation statements)

References 73 publications

(98 reference statements)

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“…Thus, pyroptosis is an immune-stimulatory form of cell death and can synergize with immune checkpoint agents to improve the efficacy of immune therapy. Recently, metformin has been reported to induce pyroptosis in cancer cells [134,135]. Given that metformin promotes antitumor immunity and improves efficacy of ICIs in malignant cancers [136][137][138][139], it is possibly that induction of pyroptosis of cancer cells by metformin may reprogram TIME toward "infiltrated-inflamed".…”

Section: Induction Of Pyroptotic Cell Death By Immune Therapymentioning

confidence: 99%

Pyroptosis: a new paradigm of cell death for fighting against cancer

Tan

Chen

et al. 2021

J Exp Clin Cancer Res

323

217

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Background Unraveling the mystery of cell death is one of the most fundamental progresses of life sciences during the past decades. Regulated cell death (RCD) or programmed cell death (PCD) is not only essential in embryonic development, but also plays an important role in the occurrence and progression of diseases, especially cancers. Escaping of cell death is one of hallmarks of cancer. Main body Pyroptosis is an inflammatory cell death usually caused by microbial infection, accompanied by activation of inflammasomes and maturation of pro-inflammatory cytokines interleukin-1β (IL-1β) and interleukin-18 (IL-18). Gasdermin family proteins are the executors of pyroptosis. Cytotoxic N-terminal of gasdermins generated from caspases or granzymes proteases mediated cleavage of gasdermin proteins oligomerizes and forms pore across cell membrane, leading to release of IL-1β, IL-18. Pyroptosis exerts tumor suppression function and evokes anti-tumor immune responses. Therapeutic regimens, including chemotherapy, radiotherapy, targeted therapy and immune therapy, induce pyroptosis in cancer, which potentiate local and systemic anti-tumor immunity. On the other hand, pyroptosis of normal cells attributes to side effects of anti-cancer therapies. Conclusion In this review, we focus on the regulatory mechanisms of pyroptosis and the tumor suppressive function of pyroptosis. We discuss the attribution of pyroptosis in reprogramming tumor microenvironments and restoration of anti-tumor immunity and its potential application in cancer immune therapy.

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Section: Induction Of Pyroptotic Cell Death By Immune Therapymentioning

confidence: 99%

Pyroptosis: a new paradigm of cell death for fighting against cancer

Tan

Chen

et al. 2021

J Exp Clin Cancer Res

323

217

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“…Many previous studies have focused on cellular oxidative stress as a primary mechanism for positive effects of metformin on colon cancer. [ 17,32,46 ] However, disturbances in the SIRT3 activity and expression might result in mitochondrial dysfunction and cell death. [ 47 ] However, there is no study regarding the underlying metformin mechanism against the CRC cells and its effects on enzyme Sirt3.…”

Section: Discussionmentioning

confidence: 99%

“…[ 17 ] Previous studies have shown that metformin can exert antineoplastic effects by recruiting the kinase enzyme activated by adenosine monophosphate (AMPK) and reducing the phosphorylation of protein kinase B, mammalian target of rapamycin (mTOR), and p70S6k in different types of tumors. [ 18,19 ] In addition, metformin regulates apoptosis signaling [ 20 ] by inhibiting phosphorylation of BAD and Bcl‐2, procaspase 9, procaspase 3, and procaspase 7, and upregulation of BAD, cytochrome c, and Apaf‐1 protein. [ 21,22 ] However, metformin is capable of affecting the mitochondrial function.…”

Section: Introductionmentioning

confidence: 99%

Cytotoxicity of metformin against HT29 colon cancer cells contributes to mitochondrial Sirt3 upregulation

Khodaei

Hosseini

Omidi

et al. 2020

J Biochem & Molecular Tox

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Cancer and diabetes, the two mitochondria‐related diseases, have recently been linked to silent mating‐type information regulation 2 homolog 3 (SIRT3) activity irregularities. In this study, the effect of metformin, an antidiabetic with anticancer properties, has been evaluated on mitochondrial functionality markers, cell death pathways, and SIRT3 enzyme activity in the colon cancer cell line, HT‐29, and human embryonic kidney cells (HEK 293). HT‐29 cells were treated with metformin (5, 10, 20, 40, and 80 µM) for 24, 48, and 72 h for measuring the IC50 concentration. Reactive oxygen species (ROS) production, apoptosis, mitochondrial membrane potential, SIRT3 activity, and expression were evaluated against the colon cancer cell line, HT‐29. Results indicated a higher ROS production at 6 than 12 h with metformin treatment. Metformin modified the mitochondrial membrane potential, resulting in cell death induction. Results from SIRT3 activity and expression showed that metformin increased its activity and expression in cancer cells. In conclusion, metformin in HT‐29 cells disturbed the mitochondrial activity via increased ROS levels and SIRT3 activity, and these rapid modifications may play a key role in its cytotoxic property.

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“…GSDME-NT can be stimulated by caspase-3, which is similar to the GSDMD-NT, leading to the formation of pores in the cellular membrane region ( Fig. 1 ) [50] , [51] . The actual role of GSDME in stimulating pyroptosis upon apoptosis has largely been constrained in the extensive investigations [51] .…”

Section: Introductionmentioning

confidence: 97%

“…1 ) [50] , [51] . The actual role of GSDME in stimulating pyroptosis upon apoptosis has largely been constrained in the extensive investigations [51] . During the mitochondrial apoptotic process, GSDME plays a redundant role in channel formation.…”

Section: Introductionmentioning

confidence: 99%