https://doi.org/10.4081/ejh.2023.3612
Metformin sensitises osteosarcoma to chemotherapy via the IGF-1R/miR-610/FEN1 pathway
Submitted: 17 November 2022
Accepted: 13 May 2023
Published: 17 May 2023
Accepted: 13 May 2023
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All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.
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Metformin can enhance cancer cell chemosensitivity to anticancer drugs. IGF-1R is involved in cancer chemoresistance. The current study aimed to elucidate the role of metformin in osteosarcoma (OS) cell chemosensitivity modulation and identify its underlying mechanism in IGF-1R/miR-610/FEN1 signalling. IGF-1R, miR-610, and FEN1 were aberrantly expressed in OS and participated in apoptosis modulation; this effect was abated by metformin treatment. Luciferase reporter assays confirmed that FEN1 is a direct target of miR-610. Moreover, metformin treatment decreased IGF-1R and FEN1 but elevated miR-610 expression. Metformin sensitised OS cells to cytotoxic agents, while FEN1 overexpression partly compromised metformin’s sensitising effects. Furthermore, metformin was observed to enhance adriamycin’s effects in a murine xenograft model. Metformin enhanced OS cell sensitivity to cytotoxic agents via the IGF-1R/miR-610/FEN1 signalling axis, highlighting its potential as an adjuvant during chemotherapy.
Damron TA, Ward WG, Stewart A. Osteosarcoma, chondrosarcoma, and Ewing's sarcoma: National Cancer Data Base Report. Clin Orthop Relat Res 2007;459:40-7.
DOI: https://doi.org/10.1097/BLO.0b013e318059b8c9
Simpson S, Dunning MD, de Brot S, Grau-Roma L, Mongan NP, Rutland CS. Comparative review of human and canine osteosarcoma: morphology, epidemiology, prognosis, treatment and genetics. Acta Vet Scand 2017;59:71.
DOI: https://doi.org/10.1186/s13028-017-0341-9
Bacci G, Briccoli A, Rocca M, Ferrari S, Donati D, Longhi A, et al. Neoadjuvant chemotherapy for osteosarcoma of the extremities with metastases at presentation: recent experience at the Rizzoli Institute in 57 patients treated with cisplatin, doxorubicin, and a high dose of methotrexate and ifosfamide. Ann Oncol 2003;14:1126-34.
DOI: https://doi.org/10.1093/annonc/mdg286
Czader M, Orazi A. Therapy-related myeloid neoplasms. Am J Clin Pathol 2009;132:410-25.
DOI: https://doi.org/10.1309/AJCPD85MCOHHCOMQ
Travis LB, Demark Wahnefried W, Allan JM, Wood ME, Ng AK. Aetiology, genetics and prevention of secondary neoplasms in adult cancer survivors. Nat Rev Clin Oncol 2013;10:289-301.
DOI: https://doi.org/10.1038/nrclinonc.2013.41
Bramwell VH. Osteosarcomas and other cancers of bone. Curr Opin Oncol 2000;12:330-6.
DOI: https://doi.org/10.1097/00001622-200007000-00009
Li S, Sun W, Wang H, Zuo D, Hua Y, Cai Z. Research progress on the multidrug resistance mechanisms of osteosarcoma chemotherapy and reversal. Tumour Biol 2015;36:1329-38.
DOI: https://doi.org/10.1007/s13277-015-3181-0
Wang G, Sun M, Jiang Y, Zhang T, Sun W, Wang H, et al. Anlotinib, a novel small molecular tyrosine kinase inhibitor, suppresses growth and metastasis via dual blockade of VEGFR2 and MET in osteosarcoma. Int J Cancer 2019;145:979-93.
DOI: https://doi.org/10.1002/ijc.32180
Yu Z, Li N, Jiang K, Zhang N, Yao LL. MiR-100 up-regulation enhanced cell autophagy and apoptosis induced by cisplatin in osteosarcoma by targeting mTOR. Eur Rev Med Pharmacol Sci 2018;22:5867-73.
Zhao C, Zhang Q, Yu T, Sun S, Wang W, Liu G. Hypoxia promotes drug resistance in osteosarcoma cells via activating AMP-activated protein kinase (AMPK) signaling. J Bone Oncol 2016;5:22-9.
DOI: https://doi.org/10.1016/j.jbo.2016.01.002
Morris A. Diabetes: Systemic effects of metformin revealed. Nat Rev Endocrinol 2017;13:562.
DOI: https://doi.org/10.1038/nrendo.2017.109
Suwei D, Liang Z, Zhimin L, Ruilei L, Yingying Z, Zhen L, et al. NLK functions to maintain proliferation and stemness of NSCLC and is a target of metformin. J Hematol Oncol 2015;8:120.
DOI: https://doi.org/10.1186/s13045-015-0203-8
Sambi M, Samuel V, Qorri B, Haq S, Burov SV, Markvicheva E, et al. A triple combination of metformin, acetylsalicylic acid, and oseltamivir phosphate impacts tumour spheroid viability and upends chemoresistance in triple-negative breast cancer. Drug Des Devel Ther 2020;14:1995-2019.
DOI: https://doi.org/10.2147/DDDT.S242514
Anisimov VN. Metformin for prevention and treatment of colon cancer: a reappraisal of experimental and clinical data. Curr Drug Targets 2016;17:439-46.
DOI: https://doi.org/10.2174/1389450116666150309113305
Rizos CV, Elisaf MS. Metformin and cancer. Eur J Pharmacol 2013;705:96-108.
DOI: https://doi.org/10.1016/j.ejphar.2013.02.038
Ghavami G, Kiasari RE, Pakzad F, Sardari S. Effect of metformin alone and in combination with etoposide and epirubicin on proliferation, apoptosis, necrosis, and migration of B-CPAP and SW cells as thyroid cancer cell lines. Res Pharm Sci 2023;18:185-201.
DOI: https://doi.org/10.4103/1735-5362.367797
Hong XL, Yu TC, Huang XW, Wang JL, Sun TT, Yan TT, et al. Metformin abrogates Fusobacterium nucleatum-induced chemoresistance in colorectal cancer by inhibiting miR-361-5p/sonic hedgehog signaling-regulated stemness. Br J Cancer 2023;128:363-74.
DOI: https://doi.org/10.1038/s41416-022-02044-6
Huang S, He T, Yang S, Sheng H, Tang X, Bao F, et al. Metformin reverses chemoresistance in non-small cell lung cancer via accelerating ubiquitination-mediated degradation of Nrf2. Transl Lung Cancer Res 2020;9:2337-55.
DOI: https://doi.org/10.21037/tlcr-20-1072
Matà R, Palladino C, Nicolosi ML, Lo Presti AR, Malaguarnera R, Ragusa M, et al. IGF-I induces upregulation of DDR1 collagen receptor in breast cancer cells by suppressing MIR-199a-5p through the PI3K/AKT pathway. Oncotarget 2016;7:7683-700.
DOI: https://doi.org/10.18632/oncotarget.6524
Vaezi MA, Eghtedari AR, Safizadeh B, Babaheidarian P, Salimi V, Adjaminezhad-Fard F, et al. Evaluating the local expression pattern of IGF-1R in tumor tissues and the circulating levels of IGF-1, IGFBP-1, and IGFBP-3 in the blood of patients with different primary bone tumors. Front Oncol 2022;12:1096438.
DOI: https://doi.org/10.3389/fonc.2022.1096438
Duan Z, Choy E, Harmon D, Yang C, Ryu K, Schwab J, et al. Insulin-like growth factor-I receptor tyrosine kinase inhibitor cyclolignan picropodophyllin inhibits proliferation and induces apoptosis in multidrug resistant osteosarcoma cell lines. Mol Cancer Ther 2009;8:2122-30.
DOI: https://doi.org/10.1158/1535-7163.MCT-09-0115
Luk F, Yu Y, Walsh WR, Yang JL. IGF1R-targeted therapy and its enhancement of doxorubicin chemosensitivity in human osteosarcoma cell lines. Cancer Invest 2011;29:521-32.
DOI: https://doi.org/10.3109/07357907.2011.606252
Pan YH, Jiao L, Lin CY, Lu CH, Li L, Chen HY, et al. Combined treatment with metformin and gefitinib overcomes primary resistance to EGFR-TKIs with EGFR mutation via targeting IGF-1R signaling pathway. Biologics 2018;12:75-86.
DOI: https://doi.org/10.2147/BTT.S166867
Dong S, Xiao Y, Ma X, He W, Kang J, Peng Z, et al. miR-193b increases the chemosensitivity of osteosarcoma cells by promoting FEN1-mediated autophagy. Onco Targets Ther 2019;12:10089-98.
DOI: https://doi.org/10.2147/OTT.S219977
Soghli N, Ferns GA, Sadeghsoltani F, Qujeq D, Yousefi T, Vaghari-Tabari M. MicroRNAs and osteosarcoma: Potential targets for inhibiting metastasis and increasing chemosensitivity. Biochem Pharmacol 2022;201:115094.
DOI: https://doi.org/10.1016/j.bcp.2022.115094
Jin C, Feng Y, Ni Y, Shan Z. MicroRNA-610 suppresses osteosarcoma oncogenicity via targeting TWIST1 expression. Oncotarget 2017;8:56174-84.
DOI: https://doi.org/10.18632/oncotarget.17045
Livak KJ, Schmittgen TD. Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) method. Methods 2001;25:402-8.
DOI: https://doi.org/10.1006/meth.2001.1262
Shi Z, Liang YJ, Chen ZS, Wang XW, Wang XH, Ding Y, et al. Reversal of MDR1/P-glycoprotein-mediated multidrug resistance by vector-based RNA interference in vitro and in vivo. Cancer Biol Ther 2006;5:39-47.
DOI: https://doi.org/10.4161/cbt.5.1.2236
Huang J, Ni J, Liu K, Yu Y, Xie M, Kang R, et al. HMGB1 promotes drug resistance in osteosarcoma. Cancer Res 2012;72:230-8.
DOI: https://doi.org/10.1158/0008-5472.CAN-11-2001
Bao X, Zhao L, Guan H, Li F. Inhibition of LCMR1 and ATG12 by demethylation-activated miR-570-3p is involved in the anti-metastasis effects of metformin on human osteosarcoma. Cell Death Dis 2018;9:611.
DOI: https://doi.org/10.1038/s41419-018-0620-z
Balakrishnan L, Bambara RA. Flap endonuclease 1. Annu Rev Biochem 2013;82:119-38.
DOI: https://doi.org/10.1146/annurev-biochem-072511-122603
Guo E, Ishii Y, Mueller J, Srivatsan A, Gahman T, Putnam CD, et al. FEN1 endonuclease as a therapeutic target for human cancers with defects in homologous recombination. Proc Natl Acad Sci USA 2020;117:19415-24.
DOI: https://doi.org/10.1073/pnas.2009237117
Otoukesh B, Boddouhi B, Moghtadaei M, Kaghazian P, Kaghazian M. Novel molecular insights and new therapeutic strategies in osteosarcoma. Cancer Cell Int 2018;18:158.
DOI: https://doi.org/10.1186/s12935-018-0654-4
Li B, Zhou P, Xu K, Chen T, Jiao J, Wei H, et al. Metformin induces cell cycle arrest, apoptosis and autophagy through ROS/JNK signaling pathway in human osteosarcoma. Int J Biol Sci 2020;16:74-84.
DOI: https://doi.org/10.7150/ijbs.33787
Li Z, Wang L, Luo N, Zhao Y, Li J, Chen Q, et al. Metformin inhibits the proliferation and metastasis of osteosarcoma cells by suppressing the phosphorylation of Akt. Oncol Lett 2018;15:7948-54.
DOI: https://doi.org/10.3892/ol.2018.8297
Shanchun H, You P, Sujuan N, Xuebing Z, Yijie B, Xiaohui X, et al. Integrative analyses of biomarkers and pathways for metformin reversing cisplatin resistance in head and neck squamous cell carcinoma cells. Arch Oral Biol 2023;147:105637.
DOI: https://doi.org/10.1016/j.archoralbio.2023.105637
El-Awady RA, Semreen MH, Saber-Ayad MM, Cyprian F, Menon V, Al-Tel TH. Modulation of DNA damage response and induction of apoptosis mediates synergism between doxorubicin and a new imidazopyridine derivative in breast and lung cancer cells. DNA Repair (Amst) 2016;37:1-11.
DOI: https://doi.org/10.1016/j.dnarep.2015.10.004
Forgie BN, Prakash R, Telleria CM. Revisiting the anti-cancer toxicity of clinically approved platinating derivatives. Int J Mol Sci 2022;23:15410.
DOI: https://doi.org/10.3390/ijms232315410
Jeggo PA, Löbrich M. How cancer cells hijack DNA double-strand break repair pathways to gain genomic instability. Biochem J 2015;471:1-11.
DOI: https://doi.org/10.1042/BJ20150582
Brown JS, O'Carrigan B, Jackson SP, Yap TA. Targeting DNA repair in cancer: Beyond PARP inhibitors. Cancer Discov 2017;7:20-37.
DOI: https://doi.org/10.1158/2159-8290.CD-16-0860
Jeong YK, Kim MS, Lee JY, Kim EH, Ha H. Metformin radiosensitizes p53-deficient colorectal cancer cells through induction of G2/M arrest and inhibition of DNA repair proteins. PLoS One 2015;10:e0143596.
DOI: https://doi.org/10.1371/journal.pone.0143596
Kametani Y, Takahata C, Narita T, Tanaka K, Iwai S, Kuraoka I. FEN1 participates in repair of the 5'-phosphotyrosyl terminus of DNA single-strand breaks. Carcinogenesis 2016;37:56-62.
DOI: https://doi.org/10.1093/carcin/bgv159
Ward TA, McHugh PJ, Durant ST. Small molecule inhibitors uncover synthetic genetic interactions of human flap endonuclease 1 (FEN1) with DNA damage response genes. PLoS One 2017;12:e0179278.
DOI: https://doi.org/10.1371/journal.pone.0179278
Ethics Approval
This study was approved by the Ethics Committee of the Third Affiliated Hospital of Kunming Medical University and the Kunming Medical University Animal Care and Use Committee (Protocol no. YTH2019-026); all patients provided written informed consent and authorized biological specimen use, in accordance with the Declaration of Helsinki.Supporting Agencies
National Natural Science Foundation of China , Natural Science Foundation of Jiangsu Province, Basic Research Program of Xuzhou Health Commission, Development Foundation of Affiliated Hospital of Xuzhou Medical University, Applied basic research of Yunnan Science & Technology Agency-Joint Funds of Yunnan Science & Technology Agency and Kunming Medical UniversityHow to Cite
Dong, S., Xiao, Y., Zhu, Z., Ma, X., Peng, Z., Kang, J., … Li, Z. (2023). Metformin sensitises osteosarcoma to chemotherapy <em>via</em> the IGF-1R/miR-610/FEN1 pathway. European Journal of Histochemistry, 67(2). https://doi.org/10.4081/ejh.2023.3612
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