A Cohort Study of Antihyperglycemic Medication Exposure and Gastric Cancer Risk

Dulskas, Audrius; Patašius, Aušvydas; Kaceniene, Auguste; Linkeviciute-Ulinskiene, Donata; Zabulienė, Lina; Smailytė, Giedrė

doi:10.3390/jcm9020435

Cited by 16 publications

(18 citation statements)

References 33 publications

(52 reference statements)

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“…20 Previous population-based researches shown that patients with type 2 diabetes mellitus who use metformin as the sole drug have a significantly reduced risk of developing GC. 2,3 Metformin also has the potential ability to inhibit a variety of other tumours; 6,7,21 however, relatively few studies have focused on GC. Consequently, the mechanism by which metformin inhibits tumour activity in GC remains unclear.…”

Section: Discussionmentioning

confidence: 99%

<p>Metformin Promotes Beclin1-Dependent Autophagy to Inhibit the Progression of Gastric Cancer</p>

Liu¹,

Yang²,

Chen³

et al. 2020

OTT

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Background: Metformin is the first-line blood sugar control drug for type 2 diabetes, but recent epidemiological studies have shown that it inhibits the growth of a variety of tumours. However, few studies have examined metformin effects on gastric cancer (GC), and the anticancer mechanism has not been fully elucidated. Materials and Methods: We examined the inhibitory effect of metformin on GC cells by cell proliferation, migration and invasion assay. Transmission electron microscopy, confocal microscopy and Western blotting confirmed that metformin enhanced beclin1-dependent autophagy in gastric cancer cells. TCGA database and tissue chip analysis confirmed the differential expression of beclin1 in GC and adjacent tissues. Relevant functional tests verified the role of beclin1 as a tumour suppressor gene in GC. Western blotting, cell proliferation, cell migration and invasion were used to verify that metformin enhances autophagy in GC cells through the AMPK-mTOR signalling pathway. Xenograft tumour models were constructed to explore the inhibitory effect of metformin and the role of beclin1 as a suppressor on GC in vivo. Results: In this study, we observed that metformin inhibits proliferation, migration and invasion of GC cells. Metformin could also promote beclin1-dependent autophagy in GC cells. We further discovered that beclin1 expression was downregulated in GC and that its low expression was associated with poor prognosis. Beclin1 acts as a tumour suppressor that inhibits the malignant phenotypes of GC cells in vitro and in vivo. Furthermore, we verified that metformin can upregulate beclin1-mediated autophagy to inhibit GC cells through the AMPK-mTOR signalling pathway. Conclusion: In summary, the results revealed the role of autophagy in metformin inhibition of gastric cancer and suggest that beclin1 may be a potential target for gastric cancer therapy.

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Section: Discussionmentioning

confidence: 99%

<p>Metformin Promotes Beclin1-Dependent Autophagy to Inhibit the Progression of Gastric Cancer</p>

Liu¹,

Yang²,

Chen³

et al. 2020

OTT

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“…Primary or acquired drug resistance is the major challenge to GC therapy, which inevitably leads to recurrence and poor prognosis in clinic. Previous studies demonstrated that metformin exhibited anti-cancer properties, especially in patients with diabetes ( 22 , 23 ). Mitophagy acts as a double-edged sword in the chemotherapy for gastric cancer ( 24 , 25 ).…”

Section: Discussionmentioning

confidence: 99%

Metformin-induced AMPK activation promotes cisplatin resistance through PINK1/Parkin dependent mitophagy in gastric cancer

Xiao

Wang

et al. 2022

Front. Oncol.

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Gastric cancer (GC) is one of the most common tumors worldwide, and cisplatin is a standard chemotherapeutic reagent for GC treatment. However, chemoresistance is an inherent challenge which limits its application and effectiveness in clinic. This study aims to investigate the mechanism of metformin-induced cisplatin resistance in GC. Intriguingly, the upregulation of mitophagy markers, mitochondrial fission, autophagy and mitophagosome were observed in SGC-7901/DDP cells compared to those in the SGC-7901 cells. Treatment with metformin significantly increased mitochondrial fission and mitophagy in both AGS and SGC-7901 cells, resulting in decreased ATP production, which unexpectedly protected GC cells against the cytotoxicity of cisplatin. In contrast, application of Chloroquine and 3-methyladenine, two inhibitors of autophagy, significantly alleviated the protective effect of metformin on SGC-7901 and AGS cells against cytotoxicity of cisplatin. Moreover, metformin also stimulated the phosphorylation of AMPK (Thr172) and increased the expression of mitophagy markers including Parkin and PINK1 in the AMPK signaling-dependent manner. Consistently, the cell viability and cell apoptosis assay showed that metformin-induced cisplatin resistance was prevented by knockdown of AMPKα1. Taken together, all data in this study indicate that metformin induced AMPK activation and PINK1/Parkin dependent mitophagy, which may contribute to the progression of cisplatin resistance in GC.

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“…MET is a first-choice drug for type 2 diabetes treatment with high safety, tolerability, and efficacy, and it has been shown a notable relationship between the duration of use of MET and a lower risk of gastrointestinal cancer in patients with type 2 diabetes [72,73]. A significant pathway in MET effect on glucose metabolism and also on anti-tumor processes is the AMPK/mTOR pathway [74].…”

Section: Gastrointestinal Cancer (Gc)mentioning

confidence: 99%

Effects of metformin on cancers in experimental and clinical studies: Focusing on autophagy and AMPK/mTOR Signaling Pathways

Zamanian,

Golmohammadi,

Yumashev

et al. 2024

Preprint

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Metformin (MET) is a preferred drug for the treatment of type 2 diabetes mellitus. Recent studies show that apart from its blood glucose-lowering effects, it also inhibits the development of various tumours, by inducing autophagy. Further, various studies have confirmed the inhibitory effects of MET on cancer cell lines’ propagation, migration, and invasion. However, despite the many publications on the anticancer potential of MET, there is no existing comprehensive review and account of its autophagy-associated anticancer activity, this review. This review noted that MET exerts its anticancer effects by regulating key signalling pathways such as phosphoinositide 3-kinase (PI3K), LC3-I and LC3-II, Beclin-1, p53, and the autophagy-related gene (ATG), inhibiting the mTOR protein, downregulating the expression of p62/SQSTM1, and blockage of the cell cycle at the G0/G1. Moreover, MET can stimulate autophagy through pathways associated with the 5′ adenosine monophosphate-activated protein kinase (AMPK), thereby inhibiting he development and progression of various human cancers, including hepatocellular carcinoma, prostate cancer, pancreatic cancer, osteosarcoma, myeloma, and non-small cell lung cancer. Therefore, this detailed review provides a framework for further investigations that may appraise the autophagy-induced anticancer potential of MET and its repurposing for cancer treatment.

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A Cohort Study of Antihyperglycemic Medication Exposure and Gastric Cancer Risk

Cited by 16 publications

References 33 publications

<p>Metformin Promotes Beclin1-Dependent Autophagy to Inhibit the Progression of Gastric Cancer</p>

<p>Metformin Promotes Beclin1-Dependent Autophagy to Inhibit the Progression of Gastric Cancer</p>

Metformin-induced AMPK activation promotes cisplatin resistance through PINK1/Parkin dependent mitophagy in gastric cancer

Effects of metformin on cancers in experimental and clinical studies: Focusing on autophagy and AMPK/mTOR Signaling Pathways

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