For colorectal cancer patients with type II diabetes, could metformin improve the survival rate? A meta-analysis

Cheng, Yifan; Chen, Yanyu; Zhou, Chong‐Jun; Shen, Leibin; Tu, Fuyang; Xu, Jingxuan; Liu, Changbao

doi:10.1016/j.clinre.2019.06.009

Cited by 24 publications

(27 citation statements)

References 40 publications

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“…In a meta-analysis, patients with diabetes have an 18% lower 5-year survival rate in CRC [ 33 ]. Intriguingly, metformin improves the overall and cancer-specific survival rates of patients with CRC and diabetes [ 34 ]. Nevertheless, there are conflicting results regarding the effects of metformin on the incidence and prognosis of cancer [ 21 , 35 , 36 ].…”

Section: Discussionmentioning

confidence: 99%

Lipopolysaccharide promotes metastasis via acceleration of glycolysis by the nuclear factor-κB/snail/hexokinase3 signaling axis in colorectal cancer

Qian

Zhang

et al. 2021

Cancer Metab

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Background Cancer cell is generally characterized by enhanced glycolysis. Inflammasome activation is interaction with glycolysis. The concentration of lipopolysaccharide (LPS), a classic inflammasome activator, is significantly higher in colorectal cancer tissue than in normal intestinal mucosa. However, the mechanism of LPS on glycolysis and metastasis has not been fully elucidated. This study aimed to investigate the roles of LPS on inflammasome activation, glycolysis, and metastasis, and unravel metformin’s potential in treatment of CRC. Methods We detected inflammasome activation and cell motility following LPS exposure in CRC cell lines. Glycolysis analysis was performed, and the key glycolytic rate-limiting enzymes were detected. Dual-luciferase reporter gene assay, co-immunoprecipitation, chromatin immunoprecipitation (ChIP) analysis, and ChIP-reChIP assay were performed to identify the specific mechanisms of LPS on glycolysis. Mouse metastasis models were used to determine the effects of LPS and metformin on metastasis. Correlation analysis of the expression of various molecules was performed in 635 CRC samples from The Cancer Genome Atlas and 83 CRC samples from our lab. Results LPS activates caspase-1 through NF-κB and upregulates the expression of Snail and HK3 depending on caspase-1 activation. LPS potentiates migration and invasion depending on accelerated glycolysis, which could be reversed by knockdown of glycolytic rate-limiting enzyme HK3. Nuclear Snail is upregulated by NF-κB under LPS treatment and then forms a complex with NF-κB, then directly binds to the HK3 promoter region to upregulate the expression of HK3. Metformin suppresses the NF-κB/Snail/HK3 signaling axis that is activated by LPS and then inhibits LPS-induced metastasis. In vivo, LPS-treated cells form more metastasis in the lungs of mice, and metformin completely reverses this effect of LPS. Conclusion LPS activates inflammasomes in cancer cells through NF-κB and promotes metastasis through glycolysis enhanced by the NF-κB/Snail/HK3 signaling pathway in CRC. Metformin could prevent this effect of LPS.

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Section: Discussionmentioning

confidence: 99%

Lipopolysaccharide promotes metastasis via acceleration of glycolysis by the nuclear factor-κB/snail/hexokinase3 signaling axis in colorectal cancer

Qian

Zhang

et al. 2021

Cancer Metab

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“…Epidemiological studies have also suggested that patients administered metformin have a lower risk for cancer 6 . Results of a previous meta‐analysis suggested that metformin could increase the survival rate of CRC patients with type II diabetes mellitus 7 . Metformin can prevent hyperinsulinemia‐induced adverse prognosis in chemotherapy for digestive tract cancer (eg, CRC) 8 .…”

Section: Introductionmentioning

confidence: 99%

“…6 Results of a previous meta-analysis suggested that metformin could increase the survival rate of CRC patients with type II diabetes mellitus. 7 Metformin can prevent hyperinsulinemia-induced adverse prognosis in chemotherapy for digestive tract cancer (eg, CRC). 8 Metformin is an adenosine monophosphate-activated protein kinase (AMPK) capable of inhibiting Erk activation and apoptosis in cancer cells.…”

Section: Introductionmentioning

confidence: 99%

Metformin revert insulin‐induced oxaliplatin resistance by activating mitochondrial apoptosis pathway in human colon cancer HCT116 cells

Liu

Yan

et al. 2020

Cancer Medicine

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Background: Several studies have suggested that drug resistance in colon cancer patients with diabetes may be associated with long-term insulin administration, which in turn decreases the survival rate. Metformin is a commonly used drug to treat diabetes but has been recently demonstrated to have a potential therapeutic effect on colon cancer. This study aimed to elucidate the underlying mechanism by which metformin reverts insulin-induced oxaliplatin resistance in human colon cancer HCT116 cells. Methods: Two colon cancer cell lines (HCT116 and LoVo) were used to verify whether the expression of insulin receptor substrate 1 (IRS-1) could impact the half maximal inhibitory concentration (IC50) of oxaliplatin after chronic insulin treatment. The IC50 of oxaliplatin in both cell lines was measured to identify metformin sensitization to oxaliplatin. The adenosine monophosphate-activated protein kinase (AMPK) inhibitor, namely AMPK small interfering RNA, was used to block AMPK activation to identify critical proteins in the AMPK/Erk signaling pathway. Bcl-2 is a vital antiapoptotic protein involved in the mitochondrial apoptosis pathway. Finally, immunofluorescence and electron microscopy were performed to investigate how metformin affects the ultrastructural integrity of mitochondria. Results: The IC50 of oxaliplatin in HCT116 cells was noticeably increased. After the cells were treated with metformin, oxaliplatin resistance was reversed. According to the results of the western blotting assay of vital proteins involved in the classical apoptosis pathway, cleaved caspase-9 was noticeably upregulated, suggesting that the mitochondrial apoptosis pathway was activated. These results were verified by imaging of mitochondria using electron microscopy. The AMPK/Erk signaling pathway experiments revealed that the upregulation of Bcl-2 induced by insulin through Erk phosphorylation was inhibited by metformin and that such inhibition could be mitigated by the inhibition of AMPK. Conclusions: Insulin-induced oxaliplatin resistance was reversed by metformin-mediated AMPK activation. Accordingly, metformin is likely to sensitize patients with diabetes to chemotherapeutic drugs used to treat colon cancer. |

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“…In mice, metformin treatment can reduce the risk of certain cancers and decrease tumor burden in breast cancer models (Anisimov et al, 2005;Bodmer et al, 2010). In human cohorts, metformin has also shown particular promise in colorectal cancer patients, although these analyses are complicated by comorbidities such as diabetes (Cheng et al, 2020). AMPK activation is thought to reduce tumor burden in part by slowing tumor growth, while concurrently supporting the expansion and survival of TIL in the TME (Blagih et al, 2015;Eikawa et al, 2015;Wegiel et al, 2018).…”

Section: Targeting Nutrient and Oxygenmentioning

confidence: 99%

Targeting Metabolism to Improve the Tumor Microenvironment for Cancer Immunotherapy

2020

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The growing field of immune metabolism has revealed promising indications for metabolic targets to modulate anti-cancer immunity. Combination therapies involving metabolic inhibitors with immune checkpoint blockade (ICB), chemotherapy, radiation, and/or diet now offer new approaches for cancer therapy. However, it remains uncertain how to best utilize these strategies in the context of the complex tumor microenvironment (TME). Oncogene-driven changes in tumor cell metabolism can impact the TME to limit immune responses and present barriers to cancer therapy. These changes also reveal opportunities to reshape the TME by targeting metabolic pathways to favor immunity. Here we explore current strategies that shift immune cell metabolism to pro-inflammatory states in the TME and highlight a need to better replicate physiologic conditions to select targets, clarify mechanisms, and optimize metabolic inhibitors. Unifying our understanding of these pathways and interactions within the heterogenous TME will be instrumental to advance this promising field and enhance immunotherapy.

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For colorectal cancer patients with type II diabetes, could metformin improve the survival rate? A meta-analysis

Cited by 24 publications

References 40 publications

Lipopolysaccharide promotes metastasis via acceleration of glycolysis by the nuclear factor-κB/snail/hexokinase3 signaling axis in colorectal cancer

Lipopolysaccharide promotes metastasis via acceleration of glycolysis by the nuclear factor-κB/snail/hexokinase3 signaling axis in colorectal cancer

Metformin revert insulin‐induced oxaliplatin resistance by activating mitochondrial apoptosis pathway in human colon cancer HCT116 cells

Targeting Metabolism to Improve the Tumor Microenvironment for Cancer Immunotherapy

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