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International Journal of Molecular Medicine
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Article Open Access

Metformin exerts anticancer effects through the inhibition of the Sonic hedgehog signaling pathway in breast cancer

Retraction in: /10.3892/ijmm.2023.5227
  • Authors:
    • Cong Fan
    • Yunshan Wang
    • Ziming Liu
    • Ying Sun
    • Xiuwen Wang
    • Guangwei Wei
    • Junmin Wei
  • View Affiliations / Copyright

    Affiliations: Department of Chemotherapy, Cancer Center, Qilu Hospital, Shandong University, Jinan, Shandong 250012, P.R. China, Department of Human Anatomy and Key Laboratory of Experimental Teratology, Ministry of Education, Shandong University School of Medicine, Jinan, Shandong 250012, P.R. China, Department of Emergency Medicine, The Fifth People's Hospital, Jinan, Shandong 250022, P.R. China
    Copyright: © Fan et al. This is an open access article distributed under the terms of Creative Commons Attribution License [CC BY_NC 3.0].
  • Pages: 204-214
    |
    Published online on: May 21, 2015
       https://doi.org/10.3892/ijmm.2015.2217
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Abstract

Metformin, a widely prescribed antidiabetic drug, has previously been shown to lower the risk of certain types of cancer, including that of breast cancer, and to improve prognosis. Its anticancer effects, which are mediated by the activation of AMP-activated protein kinase (AMPK), have become notable. The Sonic hedgehog (Shh) signaling pathway is involved in changes in mammary ducts and malignant transformation. The aim of the present study was to elucidate the role of the Shh pathway in mediating the anticancer effects of metformin and the correlation between AMPK and the Shh pathway. We investigated the effectiveness of metformin in inhibiting the proliferation, migration, invasion and stemness of breast cancer cells in vitro using RNA extraction and reverse transcription‑polymerase chain reaction (RT-PCR), western blot analysis, cell proliferation assay, scratch-wound assay (cell migration assay), cell invasion assay, mammosphere culture and flow cytometry. In in vivo experiments, a tumor xenograft model was used to detect the effects of metformin on cancer cell proliferation. The results revealed that the treatment of breast cancer cells with metformin led to the inhibition of the Shh signaling pathway. Importantly, metformin inhibited recombinant human Shh (rhShh)‑induced cell migration, invasion, and stemness, and impaired cell proliferation both in vitro and in vivo. Furthermore, the small interfering RNA (siRNA)‑mediated downregulation of AMPK reversed the inhibitory effects of metformin on rhShh‑induced Gli-1 expression and stemness. Our findings identified a role of the Shh signaling pathway in the anticancer effects of metformin in breast cancer. Furthermore, we revealed that the metformin-mediated inhibition of the Shh signaling pathway may be dependent on AMPK.
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1 

Alexander GC, Sehgal NL, Moloney RM and Stafford RS: National trends in treatment of type 2 diabetes mellitus, 1994–2007. Arch Intern Med. 168:2088–2094. 2008. View Article : Google Scholar : PubMed/NCBI

2 

Bosco JL, Antonsen S, Sørensen HT, Pedersen L and Lash TL: Metformin and incident breast cancer among diabetic women: A population-based case-control study in Denmark. Cancer Epidemiol Biomarkers Prev. 20:101–111. 2011. View Article : Google Scholar

3 

Kisfalvi K, Eibl G, Sinnett-Smith J and Rozengurt E: Metformin disrupts crosstalk between G protein-coupled receptor and insulin receptor signaling systems and inhibits pancreatic cancer growth. Cancer Res. 69:6539–6545. 2009. View Article : Google Scholar : PubMed/NCBI

4 

Hosono K, Endo H, Takahashi H, Sugiyama M, Sakai E, Uchiyama T, Suzuki K, Iida H, Sakamoto Y, Yoneda K, et al: Metformin suppresses colorectal aberrant crypt foci in a short-term clinical trial. Cancer Prev Res (Phila). 3:1077–1083. 2010. View Article : Google Scholar

5 

Azoulay L, Dell’Aniello S, Gagnon B, Pollak M and Suissa S: Metformin and the incidence of prostate cancer in patients with type 2 diabetes. Cancer Epidemiol Biomarkers Prev. 20:337–344. 2011. View Article : Google Scholar

6 

Ben Sahra I, Laurent K, Loubat A, Giorgetti-Peraldi S, Colosetti P, Auberger P, Tanti JF, Le Marchand-Brustel Y and Bost F: The antidiabetic drug metformin exerts an antitumoral effect in vitro and in vivo through a decrease of cyclin D1 level. Oncogene. 27:3576–3586. 2008. View Article : Google Scholar : PubMed/NCBI

7 

Hirsch HA, Iliopoulos D, Tsichlis PN and Struhl K: Metformin selectively targets cancer stem cells, and acts together with chemotherapy to block tumor growth and prolong remission. Cancer Res. 69:7507–7511. 2009. View Article : Google Scholar : PubMed/NCBI

8 

Buzzai M, Jones RG, Amaravadi RK, Lum JJ, DeBerardinis RJ, Zhao F, Viollet B and Thompson CB: Systemic treatment with the antidiabetic drug metformin selectively impairs p53-deficient tumor cell growth. Cancer Res. 67:6745–6752. 2007. View Article : Google Scholar : PubMed/NCBI

9 

Shackelford DB and Shaw RJ: The LKB1-AMPK pathway: Metabolism and growth control in tumour suppression. Nat Rev Cancer. 9:563–575. 2009. View Article : Google Scholar : PubMed/NCBI

10 

Zheng L, Yang W, Wu F, Wang C, Yu L, Tang L, Qiu B, Li Y, Guo L, Wu M, et al: Prognostic significance of AMPK activation and therapeutic effects of metformin in hepatocellular carcinoma. Clin Cancer Res. 19:5372–5380. 2013. View Article : Google Scholar : PubMed/NCBI

11 

Kahn BB, Alquier T, Carling D and Hardie DG: AMP-activated protein kinase: Ancient energy gauge provides clues to modern understanding of metabolism. Cell Metab. 1:15–25. 2005. View Article : Google Scholar : PubMed/NCBI

12 

Rocha GZ, Dias MM, Ropelle ER, Osório-Costa F, Rossato FA, Vercesi AE, Saad MJ and Carvalheira JB: Metformin amplifies chemotherapy-induced AMPK activation and antitumoral growth. Clin Cancer Res. 17:3993–4005. 2011. View Article : Google Scholar : PubMed/NCBI

13 

Dowling RJ, Zakikhani M, Fantus IG, Pollak M and Sonenberg N: Metformin inhibits mammalian target of rapamycin-dependent translation initiation in breast cancer cells. Cancer Res. 67:10804–10812. 2007. View Article : Google Scholar : PubMed/NCBI

14 

Ingham PW and McMahon AP: Hedgehog signaling in animal development: Paradigms and principles. Genes Dev. 15:3059–3087. 2001. View Article : Google Scholar : PubMed/NCBI

15 

Varjosalo M and Taipale J: Hedgehog: Functions and mechanisms. Genes Dev. 22:2454–2472. 2008. View Article : Google Scholar : PubMed/NCBI

16 

Zhu AJ, Zheng L, Suyama K and Scott MP: Altered localization of Drosophila Smoothened protein activates Hedgehog signal transduction. Genes Dev. 17:1240–1252. 2003. View Article : Google Scholar : PubMed/NCBI

17 

Murone M, Rosenthal A and de Sauvage FJ: Hedgehog signal transduction: From flies to vertebrates. Exp Cell Res. 253:25–33. 1999. View Article : Google Scholar : PubMed/NCBI

18 

Kubo M, Nakamura M, Tasaki A, Yamanaka N, Nakashima H, Nomura M, Kuroki S and Katano M: Hedgehog signaling pathway is a new therapeutic target for patients with breast cancer. Cancer Res. 64:6071–6074. 2004. View Article : Google Scholar : PubMed/NCBI

19 

Onishi H and Katano M: Hedgehog signaling pathway as a therapeutic target in various types of cancer. Cancer Sci. 102:1756–1760. 2011. View Article : Google Scholar : PubMed/NCBI

20 

Jeng KS, Sheen IS, Jeng WJ, Yu MC, Hsiau HI and Chang FY: High expression of Sonic Hedgehog signaling pathway genes indicates a risk of recurrence of breast carcinoma. Onco Targets Ther. 7:79–86. 2013. View Article : Google Scholar

21 

Nakamura M, Ogo A, Yamura M, Yamaguchi Y and Nakashima H: Metformin suppresses sonic hedgehog expression in pancreatic cancer cells. Anticancer Res. 34:1765–1769. 2014.PubMed/NCBI

22 

Visvader JE: Keeping abreast of the mammary epithelial hierarchy and breast tumorigenesis. Genes Dev. 23:2563–2577. 2009. View Article : Google Scholar : PubMed/NCBI

23 

Dontu G, Abdallah WM, Foley JM, Jackson KW, Clarke MF, Kawamura MJ and Wicha MS: In vitro propagation and transcriptional profiling of human mammary stem/progenitor cells. Genes Dev. 17:1253–1270. 2003. View Article : Google Scholar : PubMed/NCBI

24 

Bombonati A and Sgroi DC: The molecular pathology of breast cancer progression. J Pathol. 223:307–317. 2011. View Article : Google Scholar :

25 

Al-Hajj M, Wicha MS, Benito-Hernandez A, Morrison SJ and Clarke MF: Prospective identification of tumorigenic breast cancer cells. Proc Natl Acad Sci USA. 100:3983–3988. 2003. View Article : Google Scholar : PubMed/NCBI

26 

O’Brien CA, Kreso A and Jamieson CH: Cancer stem cells and self-renewal. Clin Cancer Res. 16:3113–3120. 2010. View Article : Google Scholar

27 

Ailles LE and Weissman IL: Cancer stem cells in solid tumors. Curr Opin Biotechnol. 18:460–466. 2007. View Article : Google Scholar : PubMed/NCBI

28 

Kakarala M and Wicha MS: Implications of the cancer stem-cell hypothesis for breast cancer prevention and therapy. J Clin Oncol. 26:2813–2820. 2008. View Article : Google Scholar : PubMed/NCBI

29 

Gupta PB, Onder TT, Jiang G, Tao K, Kuperwasser C, Weinberg RA and Lander ES: Identification of selective inhibitors of cancer stem cells by high-throughput screening. Cell. 138:645–659. 2009. View Article : Google Scholar : PubMed/NCBI

30 

Rattan R, Graham RP, Maguire JL, Giri S and Shridhar V: Metformin suppresses ovarian cancer growth and metastasis with enhancement of cisplatin cytotoxicity in vivo. Neoplasia. 13:483–491. 2011. View Article : Google Scholar : PubMed/NCBI

31 

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

32 

Bodmer M, Meier C, Krähenbühl S, Jick SS and Meier CR: Long-term metformin use is associated with decreased risk of breast cancer. Diabetes Care. 33:1304–1308. 2010. View Article : Google Scholar : PubMed/NCBI

33 

Zakikhani M, Dowling R, Fantus IG, Sonenberg N and Pollak M: Metformin is an AMP kinase-dependent growth inhibitor for breast cancer cells. Cancer Res. 66:10269–10273. 2006. View Article : Google Scholar : PubMed/NCBI

34 

Janzer A, German NJ, Gonzalez-Herrera KN, Asara JM, Haigis MC and Struhl K: Metformin and phenformin deplete tricarboxylic acid cycle and glycolytic intermediates during cell transformation and NTPs in cancer stem cells. Proc Natl Acad Sci USA. 111:10574–10579. 2014. View Article : Google Scholar : PubMed/NCBI

35 

Ramaswamy B, Lu Y, Teng KY, Nuovo G, Li X, Shapiro CL and Majumder S: Hedgehog signaling is a novel therapeutic target in tamoxifen-resistant breast cancer aberrantly activated by PI3K/AKT pathway. Cancer Res. 72:5048–5059. 2012. View Article : Google Scholar : PubMed/NCBI

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Copy and paste a formatted citation
Spandidos Publications style
Fan C, Wang Y, Liu Z, Sun Y, Wang X, Wei G and Wei J: Metformin exerts anticancer effects through the inhibition of the Sonic hedgehog signaling pathway in breast cancer Retraction in /10.3892/ijmm.2023.5227. Int J Mol Med 36: 204-214, 2015.
APA
Fan, C., Wang, Y., Liu, Z., Sun, Y., Wang, X., Wei, G., & Wei, J. (2015). Metformin exerts anticancer effects through the inhibition of the Sonic hedgehog signaling pathway in breast cancer Retraction in /10.3892/ijmm.2023.5227. International Journal of Molecular Medicine, 36, 204-214. https://doi.org/10.3892/ijmm.2015.2217
MLA
Fan, C., Wang, Y., Liu, Z., Sun, Y., Wang, X., Wei, G., Wei, J."Metformin exerts anticancer effects through the inhibition of the Sonic hedgehog signaling pathway in breast cancer Retraction in /10.3892/ijmm.2023.5227". International Journal of Molecular Medicine 36.1 (2015): 204-214.
Chicago
Fan, C., Wang, Y., Liu, Z., Sun, Y., Wang, X., Wei, G., Wei, J."Metformin exerts anticancer effects through the inhibition of the Sonic hedgehog signaling pathway in breast cancer Retraction in /10.3892/ijmm.2023.5227". International Journal of Molecular Medicine 36, no. 1 (2015): 204-214. https://doi.org/10.3892/ijmm.2015.2217
Copy and paste a formatted citation
x
Spandidos Publications style
Fan C, Wang Y, Liu Z, Sun Y, Wang X, Wei G and Wei J: Metformin exerts anticancer effects through the inhibition of the Sonic hedgehog signaling pathway in breast cancer Retraction in /10.3892/ijmm.2023.5227. Int J Mol Med 36: 204-214, 2015.
APA
Fan, C., Wang, Y., Liu, Z., Sun, Y., Wang, X., Wei, G., & Wei, J. (2015). Metformin exerts anticancer effects through the inhibition of the Sonic hedgehog signaling pathway in breast cancer Retraction in /10.3892/ijmm.2023.5227. International Journal of Molecular Medicine, 36, 204-214. https://doi.org/10.3892/ijmm.2015.2217
MLA
Fan, C., Wang, Y., Liu, Z., Sun, Y., Wang, X., Wei, G., Wei, J."Metformin exerts anticancer effects through the inhibition of the Sonic hedgehog signaling pathway in breast cancer Retraction in /10.3892/ijmm.2023.5227". International Journal of Molecular Medicine 36.1 (2015): 204-214.
Chicago
Fan, C., Wang, Y., Liu, Z., Sun, Y., Wang, X., Wei, G., Wei, J."Metformin exerts anticancer effects through the inhibition of the Sonic hedgehog signaling pathway in breast cancer Retraction in /10.3892/ijmm.2023.5227". International Journal of Molecular Medicine 36, no. 1 (2015): 204-214. https://doi.org/10.3892/ijmm.2015.2217
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