Open Access

Effect of metformin on the proliferation, apoptosis, invasion and autophagy of ovarian cancer cells

  • Authors:
    • Ge Zou
    • Jie Bai
    • Dandan Li
    • Yan Chen
  • View Affiliations

  • Published online on: July 24, 2019     https://doi.org/10.3892/etm.2019.7803
  • Pages: 2086-2094
  • Copyright: © Zou et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

The present study evaluated the effect of metformin on the SKOV3 ovarian cancer cell line and investigated the underlying mechanism. The inhibitory rate of SKOV3 cells was analyzed by MTT assay. SKOV3 cell apoptosis rate was quantitatively measured using flow cytometry. The effect of metformin on intracellular autophagosomes was observed using electron microscopy. The migration and invasion capabilities of SKOV3 cells were assessed by cell scratch test and Transwell assay. Results demonstrated that. the proliferation rate of SKOV3 cells was significantly inhibited in a time‑ and concentration‑dependent manner following treatment with different concentrations of metformin for 24, 48 and 72 h. The number of migratory cells significantly decreased with increasing concentrations of metformin. The administration of metformin also promoted autophagy of ovarian cancer The expression level of microtubule associated protein 1 light chain 3‑α protein was markedly upregulated. The mRNA expression level of metastasis‑associated 1 (MTA1) was significantly downregulated following metformin treatment. In conclusion, metformin intervention suppressed SKOV3 proliferation and induced apoptosis in a concentration‑dependent manner. Metformin also inhibited the invasion and migration of SKOV3 cells. It was hypothesized that the underlying mechanism of metformin's effect may involve MTA1 downregulation.

References

1 

Liu H, Scholz C, Zang C, Schefe JH, Habbel P, Regierer AC, Schulz CO, Possinger K and Eucker J: Metformin and the mTOR inhibitor everolimus (RAD001) sensitize breast cancer cells to the cytotoxic effect of chemotherapeutic drugs in vitro. Anticancer Res. 32:1627–1637. 2012.PubMed/NCBI

2 

Cheng K and Hao M: Metformin inhibits TGF-β1-induced epithelial-to-mesenchymal transition via PKM2 relative-mTOR/p70s6k signaling pathway in cervical carcinoma cells. Int J Mol Sci. 17:E20002016. View Article : Google Scholar : PubMed/NCBI

3 

Gwak H, Kim Y, An H, Dhanasekaran DN and Song YS: Metformin induces degradation of cyclin D1 via AMPK/GSK3beta axis in ovarian cancer. Mol Carcinog. 56:349–358. 2017. View Article : Google Scholar : PubMed/NCBI

4 

Gajjar K, Ogden G, Mujahid MI and Razvi K: Symptoms and risk factors of ovarian cancer: A survey in primary care. ISRN Obstet Gynecol. 2012:7541972012.PubMed/NCBI

5 

Kasznicki J, Sliwinska A and Drzewoski J: Metformin in cancer prevention and therapy. Ann Transl Med. 2:572014.PubMed/NCBI

6 

Pollak M: The insulin and insulin-like growth factor receptor family in neoplasia: An update. Nat Rev Cancer. 12:159–169. 2012. View Article : Google Scholar : PubMed/NCBI

7 

Okubo K, Isono M, Asano T and Sato A: Metformin augments panobinostat's anti-bladder cancer activity by activating AMP-activated protein kinase. Transl Oncol. 12:669–682. 2019. View Article : Google Scholar : PubMed/NCBI

8 

Moon HS, Kim B, Gwak H, Suh DH and Song YS: Autophagy and protein kinase RNA-like endoplasmic reticulum kinase (PERK)/eukaryotic initiation factor 2 alpha kinase (eIF2α) pathway protect ovarian cancer cells from metformin-induced apoptosis. Mol Carcinog. 55:346–356. 2016. View Article : Google Scholar : PubMed/NCBI

9 

Livak KJ and Schmittgen TD: Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) method. Methods. 25:402–408. 2001. View Article : Google Scholar : PubMed/NCBI

10 

Binju M, Padilla MA, Singomat T, Kaur P, Suryo Rahmanto Y, Cohen PA and Yu Y: Mechanisms underlying acquired platinum resistance in high grade serous ovarian cancer - a mini review. Biochim Biophys Acta Gen Subj. 1863:371–378. 2019. View Article : Google Scholar : PubMed/NCBI

11 

Freimund AE, Beach JA, Christie EL and Bowtell DDL: Mechanisms of drug resistance in high-grade serous ovarian cancer. Hematol Oncol Clin North Am. 32:983–996. 2018. View Article : Google Scholar : PubMed/NCBI

12 

Rattan R, Giri S, Hartmann LC and Shridhar V: Metformin attenuates ovarian cancer cell growth in an AMP-kinase dispensable manner. J Cell Mol Med. 15:166–178. 2011. View Article : Google Scholar : PubMed/NCBI

13 

Yasmeen A, Beauchamp MC, Piura E, Segal E, Pollak M and Gotlieb WH: Induction of apoptosis by metformin in epithelial ovarian cancer: Involvement of the Bcl-2 family proteins. Gynecol Oncol. 121:492–498. 2011. View Article : Google Scholar : PubMed/NCBI

14 

Gotlieb WH, Saumet J, Beauchamp MC, Gu J, Lau S, Pollak MN and Bruchim I: In vitro metformin anti-neoplastic activity in epithelial ovarian cancer. Gynecol Oncol. 110:246–250. 2008. View Article : Google Scholar : PubMed/NCBI

15 

Li B, Li X, Ni Z, Zhang Y, Zeng Y, Yan X, Huang Y, He J, Lyu X, Wu Y, et al: Dichloroacetate and metformin synergistically suppress the growth of ovarian cancer cells. Oncotarget. 7:59458–59470. 2016.PubMed/NCBI

16 

Wheaton WW, Weinberg SE, Hamanaka RB, Soberanes S, Sullivan LB, Anso E, Glasauer A, Dufour E, Mutlu GM, Budigner GS and Chandel NS: Metformin inhibits mitochondrial complex I of cancer cells to reduce tumorigenesis. Elife. 3:e022422014. View Article : Google Scholar : PubMed/NCBI

17 

Ter Braak B, Siezen CL, Lee JS, Rao P, Voorhoeve C, Ruppin E, van der Laan JW and van de Water B: Insulin-like growth factor 1 receptor activation promotes mammary gland tumor development by increasing glycolysis and promoting biomass production. Breast Cancer Res. 19:142017. View Article : Google Scholar : PubMed/NCBI

18 

Bailey CJ and Turner RC: Metformin. N Engl J Med. 334:574–579. 1996. View Article : Google Scholar : PubMed/NCBI

19 

Kheirandish M, Mahboobi H, Yazdanparast M, Kamal W and Kamal MA: Anti-cancer effects of metformin: Recent evidences for its role in prevention and treatment of cancer. Curr Drug Metab. 19:793–797. 2018. View Article : Google Scholar : PubMed/NCBI

20 

Sosnicki S, Kapral M and Weglarz L: Molecular targets of metformin antitumor action. Pharmacol Rep. 68:918–925. 2016. View Article : Google Scholar : PubMed/NCBI

21 

Coccetti P, Nicastro R and Tripodi F: Conventional and emerging roles of the energy sensor Snf1/AMPK in saccharomyces cerevisiae. Microb Cell. 5:482–494. 2018. View Article : Google Scholar : PubMed/NCBI

22 

Ikhlas S and Ahmad M: Metformin: Insights into its anticancer potential with special reference to AMPK dependent and independent pathways. Life Sci. 185:53–62. 2017. View Article : Google Scholar : PubMed/NCBI

23 

Faubert B, Vincent EE, Poffenberger MC and Jones RG: The AMP-activated protein kinase (AMPK) and cancer: Many faces of a metabolic regulator. Cancer Lett. 356:165–170. 2015. View Article : Google Scholar : PubMed/NCBI

24 

Cerezo M, Tichet M, Abbe P, Ohanna M, Lehraiki A, Rouaud F, Allegra M, Giacchero D, Bahadoran P, Bertolotto C, et al: Metformin blocks melanoma invasion and metastasis development in AMPK/p53-dependent manner. Mol Cancer Ther. 12:1605–1615. 2013. View Article : Google Scholar : PubMed/NCBI

25 

Luo Q, Hu D, Hu S, Yan M, Sun Z and Chen F: In vitro and in vivo anti-tumor effect of metformin as a novel therapeutic agent in human oral squamous cell carcinoma. BMC Cancer. 12:5172012. View Article : Google Scholar : PubMed/NCBI

26 

Mizushima N and Klionsky DJ: Protein turnover via autophagy: Implications for metabolism. Ann Rev Nutr. 27:19–40. 2007. View Article : Google Scholar

27 

Baldin V, Lukas J, Marcote MJ, Pagano M and Draetta G: Cyclin D1 is a nuclear protein required for cell cycle progression in G1. Genes Dev. 7:812–821. 1993. View Article : Google Scholar : PubMed/NCBI

28 

Galluzzi L, Pietrocola F, Bravo-San Pedro JM, Amaravadi RK, Baehrecke EH, Cecconi F, Codogno P, Debnath J, Gewirtz DA, Karantza V, et al: Autophagy in malignant transformation and cancer progression. EMBO J. 34:856–880. 2015. View Article : Google Scholar : PubMed/NCBI

29 

Mathew R, Kongara S, Beaudoin B, Karp CM, Bray K, Degenhardt K, Chen G, Jin S and White E: Autophagy suppresses tumor progression by limiting chromosomal instability. Genes Dev. 21:1367–1381. 2007. View Article : Google Scholar : PubMed/NCBI

30 

Valente G, Morani F, Nicotra G, Fusco N, Peracchio C, Titone R, Alabiso O, Arisio R, Katsaros D, Benedetto C and Isidoro C: Expression and clinical significance of the autophagy proteins BECLIN 1 and LC3 in ovarian cancer. Biomed Res Int. 2014:4626582014. View Article : Google Scholar : PubMed/NCBI

31 

Giatromanolaki AN, Charitoudis GS, Bechrakis NE, Kozobolis VP, Koukourakis MI, Foerster MH and Sivridis EL: Autophagy patterns and prognosis in uveal melanomas. Mod Pathol. 24:1036–1045. 2011. View Article : Google Scholar : PubMed/NCBI

32 

Li Y, Chao Y, Fang Y, Wang J, Wang M, Zhang H, Ying M, Zhu X and Wang H: MTA1 promotes the invasion and migration of non-small cell lung cancer cells by downregulating miR-125b. J Exp Clin Cancer Res. 32:332013. View Article : Google Scholar : PubMed/NCBI

33 

Marzook H, Li DQ, Nair VS, Mudvari P, Reddy SD, Pakala SB, Santhoshkumar TR, Pillai MR and Kumar R: Metastasis-associated protein 1 drives tumor cell migration and invasion through transcriptional repression of RING finger protein 144A. J Biol Chem. 287:5615–5626. 2012. View Article : Google Scholar : PubMed/NCBI

34 

Wang H, Fan L, Wei J, Weng Y, Zhou L, Shi Y, Zhou W, Ma D and Wang C: Akt mediates metastasis-associated gene 1 (MTA1) regulating the expression of E-cadherin and promoting the invasiveness of prostate cancer cells. PloS One. 7:e468882012. View Article : Google Scholar : PubMed/NCBI

35 

Mei ML, Li QL, Chu CH, Yiu CK and Lo EC: The inhibitory effects of silver diamine fluoride at different concentrations on matrix metalloproteinases. Dent Mater. 28:903–908. 2012. View Article : Google Scholar : PubMed/NCBI

36 

Kumar R, Wang RA and Bagheri-Yarmand R: Emerging roles of MTA family members in human cancers. Semin Oncol 30 (5 Suppl 16). 30–37. 2003.

37 

Malisetty VL, Penugurti V, Panta P, Chitta SK and Manavathi B: MTA1 expression in human cancers-clinical and pharmacological significance. Biomed Pharmacother. 95:956–964. 2017. View Article : Google Scholar : PubMed/NCBI

38 

Zhou H, Xu X, Xun Q, Yu D, Ling J, Guo F, Yan Y, Shi J and Hu Y: microRNA-30c negatively regulates endometrial cancer cells by targeting metastasis-associated gene-1. Oncol Rep. 27:807–812. 2012.PubMed/NCBI

39 

Bui-Nguyen TM, Pakala SB, Sirigiri RD, Xia W, Hung MC, Sarin SK, Kumar V, Slagle BL and Kumar R: NF-kappaB signaling mediates the induction of MTA1 by hepatitis B virus transactivator protein HBx. Oncogene. 29:1179–1189. 2010. View Article : Google Scholar : PubMed/NCBI

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Copy and paste a formatted citation
APA
Zou, G., Bai, J., Li, D., & Chen, Y. (2019). Effect of metformin on the proliferation, apoptosis, invasion and autophagy of ovarian cancer cells. Experimental and Therapeutic Medicine, 18, 2086-2094. https://doi.org/10.3892/etm.2019.7803
MLA
Zou, G., Bai, J., Li, D., Chen, Y."Effect of metformin on the proliferation, apoptosis, invasion and autophagy of ovarian cancer cells". Experimental and Therapeutic Medicine 18.3 (2019): 2086-2094.
Chicago
Zou, G., Bai, J., Li, D., Chen, Y."Effect of metformin on the proliferation, apoptosis, invasion and autophagy of ovarian cancer cells". Experimental and Therapeutic Medicine 18, no. 3 (2019): 2086-2094. https://doi.org/10.3892/etm.2019.7803