Dual Anticancer Role of Metformin: an Old Drug Regulating AMPK Dependent/independent Pathways in Metabolic, Oncogenic/tumorsuppresing and Immunity Context

Overview

Journal Am J Cancer Res

Specialty Oncology

Date 2021 Dec 7

PMID 34873484

Citations 11

Authors

Maja S Misirkic Marjanovic

Ljubica M Vucicevic

Ana R Despotovic

Marina M Stamenkovic

Kristina D Janjetovic

Affiliations

Soon will be listed here.

Abstract

Metformin has been known to treat type 2 diabetes for decades and is widely prescribed antidiabetic drug. Recently, its anticancer potential has also been discovered. Moreover, metformin has low cost thus it has attained profound research interest. Comprehensing the complexity of the molecular regulatory networks in cancer provides a mode for advancement of research in cancer development and treatment. Metformin targets many pathways that play an important role in cancer cell survival outcome. Here, we described anticancer activity of metformin on the AMPK dependent/independent mechanisms regulating metabolism, oncogene/tumor suppressor signaling pathways together with the issue of clinical studies. We also provided brief overwiev about recently described metformin's role in cancer immunity. Insight in these complex molecular networks, will simplify application of metformin in clinical trials and contribute to improvement of anti-cancer therapy.

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References

Sato A, Sunayama J, Okada M, Watanabe E, Seino S, Shibuya K . Glioma-initiating cell elimination by metformin activation of FOXO3 via AMPK. Stem Cells Transl Med. 2012; 1(11):811-24. PMC: 3659661. DOI: 10.5966/sctm.2012-0058. View

Athreya A, Kalari K, Cairns J, Gaglio A, Wills Q, Niu N . Model-based unsupervised learning informs metformin-induced cell-migration inhibition through an AMPK-independent mechanism in breast cancer. Oncotarget. 2017; 8(16):27199-27215. PMC: 5432329. DOI: 10.18632/oncotarget.16109. View

Ma R, Yi B, Riker A, Xi Y . Metformin and cancer immunity. Acta Pharmacol Sin. 2020; 41(11):1403-1409. PMC: 7656961. DOI: 10.1038/s41401-020-00508-0. View

Khan A, Frigo D . A spatiotemporal hypothesis for the regulation, role, and targeting of AMPK in prostate cancer. Nat Rev Urol. 2017; 14(3):164-180. PMC: 5672799. DOI: 10.1038/nrurol.2016.272. View

Blandino G, Valerio M, Cioce M, Mori F, Casadei L, Pulito C . Metformin elicits anticancer effects through the sequential modulation of DICER and c-MYC. Nat Commun. 2012; 3:865. DOI: 10.1038/ncomms1859. View

Lu C, Chiang J, Tsai F, Hsu Y, Juan Y, Yang J . Metformin triggers the intrinsic apoptotic response in human AGS gastric adenocarcinoma cells by activating AMPK and suppressing mTOR/AKT signaling. Int J Oncol. 2019; 54(4):1271-1281. PMC: 6411354. DOI: 10.3892/ijo.2019.4704. View

Faubert B, Boily G, Izreig S, Griss T, Samborska B, Dong Z . AMPK is a negative regulator of the Warburg effect and suppresses tumor growth in vivo. Cell Metab. 2013; 17(1):113-24. PMC: 3545102. DOI: 10.1016/j.cmet.2012.12.001. View

Tan M, Wu A, Liao N, Liu M, Guo Q, Yi J . Inhibiting ROS-TFE3-dependent autophagy enhances the therapeutic response to metformin in breast cancer. Free Radic Res. 2018; 52(8):872-886. DOI: 10.1080/10715762.2018.1485075. View

Kim S, Kim S, Ku J . Metformin increases chemo-sensitivity via gene downregulation encoding DNA replication proteins in 5-Fu resistant colorectal cancer cells. Oncotarget. 2017; 8(34):56546-56557. PMC: 5593582. DOI: 10.18632/oncotarget.17798. View

10.

Ben Sahra I, Laurent K, Loubat A, Giorgetti-Peraldi S, Colosetti P, Auberger P . The antidiabetic drug metformin exerts an antitumoral effect in vitro and in vivo through a decrease of cyclin D1 level. Oncogene. 2008; 27(25):3576-86. DOI: 10.1038/sj.onc.1211024. View

11.

Yuan J, Dong X, Yap J, Hu J . The MAPK and AMPK signalings: interplay and implication in targeted cancer therapy. J Hematol Oncol. 2020; 13(1):113. PMC: 7433213. DOI: 10.1186/s13045-020-00949-4. View

12.

Xia C, He Z, Liang S, Chen R, Xu W, Yang J . Metformin combined with nelfinavir induces SIRT3/mROS-dependent autophagy in human cervical cancer cells and xenograft in nude mice. Eur J Pharmacol. 2019; 848:62-69. DOI: 10.1016/j.ejphar.2019.01.045. View

13.

Dong L, Zhou Q, Zhang Z, Zhu Y, Duan T, Feng Y . Metformin sensitizes endometrial cancer cells to chemotherapy by repressing glyoxalase I expression. J Obstet Gynaecol Res. 2012; 38(8):1077-85. DOI: 10.1111/j.1447-0756.2011.01839.x. View

14.

Salani B, Marini C, Del Rio A, Ravera S, Massollo M, Orengo A . Metformin impairs glucose consumption and survival in Calu-1 cells by direct inhibition of hexokinase-II. Sci Rep. 2013; 3:2070. PMC: 3691576. DOI: 10.1038/srep02070. View

15.

Algire C, Amrein L, Bazile M, David S, Zakikhani M, Pollak M . Diet and tumor LKB1 expression interact to determine sensitivity to anti-neoplastic effects of metformin in vivo. Oncogene. 2010; 30(10):1174-82. DOI: 10.1038/onc.2010.483. View

16.

Pierotti M, Berrino F, Gariboldi M, Melani C, Mogavero A, Negri T . Targeting metabolism for cancer treatment and prevention: metformin, an old drug with multi-faceted effects. Oncogene. 2012; 32(12):1475-87. DOI: 10.1038/onc.2012.181. View

17.

Park D . Metformin Induces Oxidative Stress-Mediated Apoptosis without the Blockade of Glycolysis in H4IIE Hepatocellular Carcinoma Cells. Biol Pharm Bull. 2019; 42(12):2002-2008. DOI: 10.1248/bpb.b19-00474. View

18.

Ren D, Qin G, Zhao J, Sun Y, Zhang B, Li D . Metformin activates the STING/IRF3/IFN-β pathway by inhibiting AKT phosphorylation in pancreatic cancer. Am J Cancer Res. 2020; 10(9):2851-2864. PMC: 7539786. View

19.

Feng Y, Ke C, Tang Q, Dong H, Zheng X, Lin W . Metformin promotes autophagy and apoptosis in esophageal squamous cell carcinoma by downregulating Stat3 signaling. Cell Death Dis. 2014; 5:e1088. PMC: 3944271. DOI: 10.1038/cddis.2014.59. View

20.

Pollak M . Targeting oxidative phosphorylation: why, when, and how. Cancer Cell. 2013; 23(3):263-4. DOI: 10.1016/j.ccr.2013.02.015. View