| Citation: |
YU Hui, LI Zhen, WANG Jia. Antitumor Effect of Metformin on Ovarian Cancer Cells[J]. Cancer Research on Prevention and Treatment, 2024, 51(1): 27-33. DOI: 10.3971/j.issn.1000-8578.2024.23.0576
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To explore the antitumor effects of metformin on ovarian cancer cells in vitro, particularly on tumor cell proliferation, cell cycle, apoptosis, migration, and possible mechanism.
Ovarian cancer cell lines (A2780, CAOV3, and SKOV3) were treated with different concentrations of metformin. Their proliferation was explored using the MTT and clone formation assays, cell migration was examined using the scratch and Transwell assays, and cell cycle and apoptosis were examined using flow cytometry. In addition, metformin’s effects on the phosphorylation of AMPK and mTOR and the expression of CXCR4 and Wnt/β-catenin protein was measured by Western blot.
The survival rates of ovarian cancer cells decreased significantly with increasing metformin concentration and metformin treatment time. The IC50 values of metformin at 48 h for A2780, CAOV3, and SKOV3 cells were 16.36, 36.65, and 43.44 mmol/L, respectively. Compared with the control group, the clone formation ability and cell migration ability of ovarian cancer cells were significantly inhibited by metformin treatment and cell cycle arrested at the G0/G1 phase, and the apoptosis rate increased. As metformin concentration increased, the expression of phosphorylated AMPK protein gradually increased, and the expression levels of phosphorylated mTOR, CXCR4, Dvl3, β-catenin, cyclin D1, and CDK1 decreased.
Metformin exerts an antitumor effect on ovarian cancer cells, which is related to the activation of AMPK to inhibit CXCR4-mediated Wnt/β-catenin signaling pathway.
Competing interests: The authors declare that they have no competing interests.
| [1] |
Siegel RL, Miller KD, Wagle NS, et al. Cancer statistics, 2023[J]. CA Cancer J Clin, 2023, 73(1): 17-48. doi: 10.3322/caac.21763
|
| [2] |
Colombo N, Sessa C, du Bois A, et al. ESMO-ESGO consensus conference recommendations on ovarian cancer: pathology and molecular biology, early and advanced stages, borderline tumours and recurrent diseasedagger[J]. Ann Oncol, 2019, 30(5): 672-705. doi: 10.1093/annonc/mdz062
|
| [3] |
Buczyńska A, Sidorkiewicz I, Krętowski AJ, et al. Metformin Intervention-A Panacea for Cancer Treatment?[J]. Cancers (Basel), 2022, 14(5): 1336. doi: 10.3390/cancers14051336
|
| [4] |
Kim YS, Choi EA, Lee JW, et al. Metformin use reduced the overall risk of cancer in diabetic patients: A study based on the Korean NHIS-HEALS cohort[J]. Nutr Metab Cardiovasc Dis, 2020, 30(10): 1714-1722. doi: 10.1016/j.numecd.2020.05.010
|
| [5] |
Hua Y, Zheng Y, Yao Y, et al. Metformin and cancer hallmarks: shedding new lights on therapeutic repurposing[J]. J Transl Med, 2023, 21(1): 403. doi: 10.1186/s12967-023-04263-8
|
| [6] |
Wen KC, Sung PL, Wu A, et al. Neoadjuvant metformin added to conventional chemotherapy synergizes anti-proliferative effects in ovarian cancer[J]. J Ovarian Res, 2020, 13(1): 95. doi: 10.1186/s13048-020-00703-x
|
| [7] |
Lu MZ, Li DY, Wang XF. Effect of metformin use on the risk and prognosis of ovarian cancer: an updated systematic review and meta-analysis[J]. Panminerva Med, 2023, 65(3): 351-361.
|
| [8] |
Li C, Liu VW, Chiu PM, et al. Reduced expression of AMPK-beta1 during tumor progression enhances the oncogenic capacity of advanced ovarian cancer[J]. Mol Cancer, 2014, 13: 49.
|
| [9] |
Wang J, Cai J, Han F, et al. Silencing of CXCR4 blocks progression of ovarian cancer and depresses canonical Wnt signaling pathway[J]. Int J Gynecol Cancer, 2011, 21(6): 981-987. doi: 10.1097/IGC.0b013e31821d2543
|
| [10] |
Nurzhan S, Bekezhankyzy Z, Ding H, et al. The Effect of Different Glucose Concentrations on the Antiproliferative Activity of Metformin in MCF-7 Breast Cancer Cells[J]. Pharmaceutics, 2023, 15(9): 2186. doi: 10.3390/pharmaceutics15092186
|
| [11] |
Papachristodoulou A, Heidegger I, Virk RK, et al. Metformin Overcomes the Consequences of NKX3.1 Loss to Suppress Prostate Cancer Progression[J]. Eur Urol, 2023. S0302-2838(23)03106-6. Online ahead of print.
|
| [12] |
Zhang J, Kuang L, Li Y, et al. Metformin Regulates TET2 Expression to Inhibit Endometrial Carcinoma Proliferation: A New Mechanism[J]. Front Oncol, 2022, 12: 856707. doi: 10.3389/fonc.2022.856707
|
| [13] |
Chen YH, Yang SF, Yang CK, et al. Metformin induces apoptosis and inhibits migration by activating the AMPK/p53 axis and suppressing PI3K/AKT signaling in human cervical cancer cells[J]. Mol Med Rep, 2021, 23(1): 88.
|
| [14] |
Urpilainen E, Puistola U, Boussios S, et al. Metformin and ovarian cancer: the evidence[J]. Ann Transl Med, 2020, 8(24): 1711. doi: 10.21037/atm-20-1060
|
| [15] |
Steinberg GR, Carling D. AMP-activated protein kinase: the current landscape for drug development[J]. Nat Rev Drug Discov, 2019, 18(7): 527-551. doi: 10.1038/s41573-019-0019-2
|
| [16] |
Gwak H, Kim Y, An H, et al. Metformin induces degradation of cyclin D1 via AMPK/GSK3beta axis in ovarian cancer[J]. Mol Carcinog, 2017, 56(2): 349-358. doi: 10.1002/mc.22498
|
| [17] |
Min X, Zhang T, Lin Y, et al. Metformin inhibits the growth of ovarian cancer cells by promoting the Parkin-induced p53 ubiquitination[J]. Biosci Rep, 2020. BSR20200679. Online ahead of print. doi: 10.1042/BSR20200679
|
| [18] |
Yang Y, Li J, Lei W, et al. CXCL12-CXCR4/CXCR7 Axis in Cancer: from Mechanisms to Clinical Applications[J]. Int J Biol Sci, 2023, 19(11): 3341-3359. doi: 10.7150/ijbs.82317
|
| [19] |
Scotton CJ, Wilson JL, Milliken D, et al. Epithelial cancer cell migration: a role for chemokine receptors?[J]. Cancer Res, 2001, 61(13): 4961-4965.
|
| [20] |
Zhang J, Huang S, Quan L, et al. Determination of Potential Therapeutic Targets and Prognostic Markers of Ovarian Cancer by Bioinformatics Analysis[J]. Biomed Res Int, 2021, 2021: 8883800.
|
| [21] |
Lim H, Kim SI, Kim EN, et al. Tissue Expression and Prognostic Role of CXCL12 and CXCR4 in High-grade Serous Ovarian Carcinoma[J]. Anticancer Res, 2023, 43(7): 3331-3340. doi: 10.21873/anticanres.16509
|
| [22] |
Liu CF, Liu SY, Min XY, et al. The prognostic value of CXCR4 in ovarian cancer: a meta-analysis[J]. PLoS One, 2014, 9(3): e92629. doi: 10.1371/journal.pone.0092629
|
| [23] |
Huang X, Hao J, Tan YQ, et al. CXC Chemokine Signaling in Progression of Epithelial Ovarian Cancer: Theranostic Perspectives[J]. Int J Mol Sci, 2022, 23(5): 2642. doi: 10.3390/ijms23052642
|
| [24] |
Zheng N, Liu W, Chen J, et al. CXCR7 is not obligatory for CXCL12-CXCR4-induced epithelial-mesenchymal transition in human ovarian cancer[J]. Mol Carcinog, 2019, 58(1): 144-155. doi: 10.1002/mc.22916
|
| [25] |
Luo N, Chen DD, Liu L, et al. CXCL12 promotes human ovarian cancer cell invasion through suppressing ARHGAP10 expression[J]. Biochem Biophys Res Commun, 2019, 518(3): 416-422. doi: 10.1016/j.bbrc.2019.07.098
|
| [26] |
Liu Y, Ren CC, Yang L, et al. Role of CXCL12-CXCR4 axis in ovarian cancer metastasis and CXCL12-CXCR4 blockade with AMD3100 suppresses tumor cell migration and invasion in vitro[J]. J Cell Physiol, 2019, 234(4): 3897-3909. doi: 10.1002/jcp.27163
|
| [27] |
Lai X, Chen J. C-X-C motif chemokine ligand 12: a potential therapeutic target in Duchenne muscular dystrophy[J]. Bioengineered, 2021, 12(1): 5428-5439. doi: 10.1080/21655979.2021.1967029
|
| [28] |
Stuermer EK, Besser M, Terberger N, et al. Side effects of frequently used oral antidiabetics on wound healing in vitro[J]. Naunyn Schmiedebergs Arch Pharmacol, 2019, 392(3): 371-380. doi: 10.1007/s00210-018-01597-9
|
| [29] |
Dirat B, Ader I, Golzio M, et al. Inhibition of the GTPase Rac1 mediates the antimigratory effects of metformin in prostate cancer cells[J]. Mol Cancer Ther, 2015, 14(2): 586-596. doi: 10.1158/1535-7163.MCT-14-0102
|
| [30] |
Zheng G, Shen Z, Xu A, et al. Synergistic Chemopreventive and Therapeutic Effects of Co-drug UA-Met: Implication in Tumor Metastasis[J]. J Agric Food Chem, 2017, 65(50): 10973-10983. doi: 10.1021/acs.jafc.7b04378
|
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