Login Register Cart 0
Generic placeholder image

Recent Patents on Anti-Cancer Drug Discovery

Editor-in-Chief

ISSN (Print): 1574-8928
ISSN (Online): 2212-3970

Back
Journal Home About Journal Editorial Board Journal Insight Current Issue Volumes/Issues
Subscribe
Research Article

Metformin Inhibits NLRP3 Inflammasome Expression and Regulates Inflammatory Microenvironment to Delay the Progression of Colorectal Cancer

Author(s): Gaojie Liu, Feixiang Wang, Yanlin Feng and Hongsheng Tang*

Volume 20, Issue 2, 2025

Published on: 09 February, 2024

Page: [213 - 222] Pages: 10

DOI: 10.2174/0115748928274081240201060643

Price: $65

Abstract

Background: Colorectal cancer is a common malignant tumor, with about one million people diagnosed with it worldwide each year. Recent studies have found that metformin can inhibit the production of inflammatory factors and regulate the polarization of immune cells. However, whether metformin can regulate the inflammatory microenvironment and delay the progression of colorectal cancer by inhibiting the inflammatory response has not been deeply studied yet.

Objectives: This study aimed to explore the molecular mechanism by which metformin inhibits the expression of NLRP3 inflammasome, regulates the inflammatory microenvironment, and delays the progression of colorectal cancer through in vitro cell experiments.

Methods: In this research, NLRP3 was knocked down in human colorectal cancer cells, and metformin was added to them. Cell proliferation ability was detected by CCK8, and cell migration and invasion abilities were assessed by Transwell assay. The apoptosis rate was determined by flow cytometry. In addition, the expression of NLRP3 inflammatory vesicles and inflammatory factors in each group of cells was studied by qRT-PCR and Western blotting. Finally, clinical colorectal cancer samples were analyzed by immunohistochemistry.

Results: The results of the study showed that NLRP3 expression was significantly increased in colorectal cancer cell lines and human colorectal cancer tissues. Knockdown of NLRP3 significantly inhibited tumor cell proliferation, migration, and invasion. In addition, the proliferation, migration and invasion of tumor cells were also significantly reduced by the addition of metformin intervention. Furthermore, qRT-PCR and WB results demonstrated that the expression of IL-1β, IL-6, TNF- α, TGF-β, and IL-10 was down-regulated in LS1034 tumor cells after NLRP3 knockdown. In addition, metformin intervention also resulted in different degrees of downregulation of NLRP3 and inflammatory factor expression (p π0.05). Notably, the reduction in inflammatory factors was more pronounced after the combination of NLRP3 knockdown and metformin intervention.

Conclusion: Metformin can inhibit the expression of NLRP3 inflammasome, thereby suppressing the expression of inflammation-related factors, reducing the damage of the inflammatory microenvironment to normal cells, and delaying the progression of colorectal cancer.

Keywords: Colorectal cancer, NLRP3, inflammation, microenvironment, metformin, apoptosis.

« Previous Next »
[1]
Daly M, Paquette I. Surveillance, epidemiology, and end results (SEER) and SEER-medicare databases: Use in clinical research for improving colorectal cancer outcomes. Clin Colon Rectal Surg 2019; 32(1): 061-8.
[http://dx.doi.org/10.1055/s-0038-1673355] [PMID: 30647547]
[2]
Möller L, Wellmann I, Stang A, Kajüter H. The epidemiology of colorectal cancer in younger and older patients. Dtsch Arztebl Int 2023; 120(16): 277-83.
[http://dx.doi.org/10.3238/arztebl.m2023.0041] [PMID: 36919357]
[3]
Wetwittayakhlang P, Golovics PA, Gonczi L, Lakatos L, Lakatos PL, Kurti Z, et al. Stable Incidence and Risk Factors of Colorectal Cancer in Ulcerative Colitis:A Population-based Cohort between 1977-2020. Clin Gastroenterol Hepatol 2024; 22(1): 191-193.e3.
[http://dx.doi.org/10.1016/j.cgh.2023.03.022] [PMID: 37004972]
[4]
Reis SK, Socca EAR, de Souza BR, Genaro SC, Durán N, Fávaro WJ. Effects of combined OncoTherad immunotherapy and probiotic supplementation on modulating the chronic inflammatory process in colorectal carcinogenesis. Tissue Cell 2022; 75: 101747.
[http://dx.doi.org/10.1016/j.tice.2022.101747] [PMID: 35149440]
[5]
Ratsimandresy RA, Indramohan M, Dorfleutner A, Stehlik C. The AIM2 inflammasome is a central regulator of intestinal homeostasis through the IL-18/IL-22/STAT3 pathway. Cell Mol Immunol 2017; 14(1): 127-42.
[http://dx.doi.org/10.1038/cmi.2016.35] [PMID: 27524110]
[6]
Kryczek I, Lin Y, Nagarsheth N, et al. IL-22(+)CD4(+) T cells promote colorectal cancer stemness via STAT3 transcription factor activation and induction of the methyltransferase DOT1L. Immunity 2014; 40(5): 772-84.
[http://dx.doi.org/10.1016/j.immuni.2014.03.010] [PMID: 24816405]
[7]
Xiao Z, Wang X, Chen X, et al. Prognostic role of preoperative inflammatory markers in postoperative patients with colorectal cancer. Front Oncol 2023; 13: 1064343.
[http://dx.doi.org/10.3389/fonc.2023.1064343] [PMID: 37064153]
[8]
Vafaei S, Taheri H, Hajimomeni Y, Fakhre Yaseri A, Abolhasani Zadeh F. The role of NLRP3 inflammasome in colorectal cancer: potential therapeutic target. Clin Transl Oncol 2022; 24(10): 1881-9.
[http://dx.doi.org/10.1007/s12094-022-02861-4] [PMID: 35689136]
[9]
Tang YL, Tao Y, Zhu L, Shen JL, Cheng H. Role of NLRP3 inflammasome in hepatocellular carcinoma: A double-edged sword. Int Immunopharmacol 2023; 118: 110107.
[http://dx.doi.org/10.1016/j.intimp.2023.110107] [PMID: 37028274]
[10]
Sun CC, Li L, Tao HQ, Jiang ZC, Wang L, Wang HJ. The role of NLRP3 inflammasome in digestive system malignancy. Front Cell Dev Biol 2022; 10: 1051612.
[http://dx.doi.org/10.3389/fcell.2022.1051612] [PMID: 36619871]
[11]
Xie S, Liang J, Zhao Y, et al. The second-generation tyrosine kinase inhibitor afatinib inhibits IL-1β secretion via blocking assembly of NLRP3 inflammasome independent of epidermal growth factor receptor signaling in macrophage. Mol Immunol 2023; 153: 135-45.
[http://dx.doi.org/10.1016/j.molimm.2022.11.009] [PMID: 36495818]
[12]
Dupaul-Chicoine J, Yeretssian G, Doiron K, et al. Control of intestinal homeostasis, colitis, and colitis-associated colorectal cancer by the inflammatory caspases. Immunity 2010; 32(3): 367-78.
[http://dx.doi.org/10.1016/j.immuni.2010.02.012] [PMID: 20226691]
[13]
Zaki MH, Vogel P, Malireddi RKS, et al. The NOD-like receptor NLRP12 attenuates colon inflammation and tumorigenesis. Cancer Cell 2011; 20(5): 649-60.
[http://dx.doi.org/10.1016/j.ccr.2011.10.022] [PMID: 22094258]
[14]
Wang CW, Huang YC, Chan FN, et al. A gut microbial metabolite of ginsenosides, compound K, induces intestinal glucose absorption and Na + /glucose cotransporter 1 gene expression through activation of cAMP response element binding protein. Mol Nutr Food Res 2015; 59(4): 670-84.
[http://dx.doi.org/10.1002/mnfr.201400688] [PMID: 25600494]
[15]
Li T, Han L, Ma S, et al. Interaction of gut microbiota with the tumor microenvironment: A new strategy for antitumor treatment and traditional Chinese medicine in colorectal cancer. Front Mol Biosci 2023; 10: 1140325.
[http://dx.doi.org/10.3389/fmolb.2023.1140325] [PMID: 36950522]
[16]
Kumar Ansu, Khandelwal Swati. Combination comprising chloroquine, metformin and statin for management of cancer, composition and methods thereof. U.S Patent 20220305000, 2022.
[17]
Youssef ME, Abd El-Fattah EE, Abdelhamid AM, et al. Interference With the AMPKα/mTOR/NLRP3 Signaling and the IL-23/IL-17 Axis Effectively Protects Against the Dextran Sulfate Sodium Intoxication in Rats: A New Paradigm in Empagliflozin and Metformin Reprofiling for the Management of Ulcerative Colitis. Front Pharmacol 2021; 12: 719984.
[http://dx.doi.org/10.3389/fphar.2021.719984] [PMID: 34489707]
[18]
Singh K, Liptrot S, Tou S, et al. A multicentre study assessing the role of routine colonoscopy after acute uncomplicated diverticulitis and the incidence of colorectal cancer diagnosis. Int J Colorectal Dis 2023; 38(1): 84.
[http://dx.doi.org/10.1007/s00384-023-04374-0] [PMID: 36976397]
[19]
Casey Y, Demb J, Enwerem N, et al. Risk of Incident and Fatal Colorectal Cancer after young-onset adenoma diagnosis: a national cohort study. Am J Gastroenterol 2023; 118(9): 1656-63.
[http://dx.doi.org/10.14309/ajg.0000000000002296] [PMID: 37053557]
[20]
Motta R, Cabezas-Camarero S, Torres-Mattos C, et al. Personalizing first-line treatment in advanced colorectal cancer: Present status and future perspectives. J Clin Transl Res 2021; 7(6): 771-85.
[PMID: 34988329]
[21]
Øgaard N, Reinert T, Henriksen TV, et al. Tumour-agnostic circulating tumour DNA analysis for improved recurrence surveillance after resection of colorectal liver metastases: A prospective cohort study. Eur J Cancer 2022; 163: 163-76.
[http://dx.doi.org/10.1016/j.ejca.2021.12.026] [PMID: 35074652]
[22]
Deng Q, Geng Y, Zhao L, et al. NLRP3 inflammasomes in macrophages drive colorectal cancer metastasis to the liver. Cancer Lett 2019; 442: 21-30.
[http://dx.doi.org/10.1016/j.canlet.2018.10.030] [PMID: 30392787]
[23]
Guo W, Sun Y, Liu W, et al. Small molecule-driven mitophagy-mediated NLRP3 inflammasome inhibition is responsible for the prevention of colitis-associated cancer. Autophagy 2014; 10(6): 972-85.
[http://dx.doi.org/10.4161/auto.28374] [PMID: 24879148]
[24]
Liang L, Sun W, Wei X, et al. Oxymatrine suppresses colorectal cancer progression by inhibiting NLRP3 inflammasome activation through mitophagy induction in vitro and in vivo. Phytother Res 2023; 37(8): 3342-62.
[http://dx.doi.org/10.1002/ptr.7808] [PMID: 36974424]
[25]
Zhang Z, Chen Y, Yin Y, et al. Candida tropicalis induces NLRP3 inflammasome activation via glycogen metabolism-dependent glycolysis and JAK-STAT1 signaling pathway in myeloid-derived suppressor cells to promote colorectal carcinogenesis. Int Immunopharmacol 2022; 113(Pt B): 109430.
[http://dx.doi.org/10.1016/j.intimp.2022.109430] [PMID: 36384075]
[26]
Wang SL, Zhang MM, Zhou H, et al. Inhibition of NLRP3 attenuates sodium dextran sulfate-induced inflammatory bowel disease through gut microbiota regulation. Biomed J 2023; 46(5): 100580.
[http://dx.doi.org/10.1016/j.bj.2023.01.004] [PMID: 36758943]
[27]
Wen J, Xuan B, Liu Y, et al. NLRP3 inflammasome-induced pyroptosis in digestive system tumors. Front Immunol 2023; 14: 1074606.
[http://dx.doi.org/10.3389/fimmu.2023.1074606] [PMID: 37081882]
[28]
Godara A, Siddiqui NS, Hachem H, Tsichlis PN, Martell RE, Saif MW. Prospective Evaluation of Effect of Metformin on Activation of AMP-activated Protein Kinase (AMPK) and Disease Control in a Sub-group Analysis of Patients with GI Malignancies. Journal of Cellular Signaling 2020; 1(2): 35-41.
[http://dx.doi.org/10.33696/Signaling.1.008] [PMID: 32601620]
[29]
Georgopoulos NS, Tolia M, Mauri D, et al. Metformin: A Promising Radiosensitizer in Neoadjuvant Rectal Cancer Treatment. Rev Recent Clin Trials 2023; 18(3): 172-80.
[http://dx.doi.org/10.2174/1574887118666230428114349] [PMID: 37132307]
[30]
Buckley CE, O’Brien RM, Nugent TS, et al. Metformin is a metabolic modulator and radiosensitiser in rectal cancer. Front Oncol 2023; 13: 1216911.
[http://dx.doi.org/10.3389/fonc.2023.1216911] [PMID: 37601689]
[31]
Gash KJ, Chambers AC, Cotton DE, Williams AC, Thomas MG. Potentiating the effects of radiotherapy in rectal cancer: the role of aspirin, statins and metformin as adjuncts to therapy. Br J Cancer 2017; 117(2): 210-9.
[http://dx.doi.org/10.1038/bjc.2017.175] [PMID: 28641310]
[32]
Sehdev A, Shih YCT, Vekhter B, Bissonnette MB, Olopade OI, Polite BN. Metformin for primary colorectal cancer prevention in patients with diabetes: A case‐control study in a US population. Cancer 2015; 121(7): 1071-8.
[http://dx.doi.org/10.1002/cncr.29165] [PMID: 25424411]
[33]
Fernandes JM, Jandrey EHF, Koyama FC, et al. Metformin as an Alternative Radiosensitizing Agent to 5-Fluorouracil During Neoadjuvant Treatment for Rectal Cancer. Dis Colon Rectum 2020; 63(7): 918-26.
[http://dx.doi.org/10.1097/DCR.0000000000001626] [PMID: 32229782]

Rights & Permissions Print Cite
Article Metrics
43
1
Wayfinder Image
© 2025 Bentham Science Publishers | Privacy Policy