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Article

Metformin facilitates BG45‑induced apoptosis via an anti‑Warburg effect in cholangiocarcinoma cells

Corrigendum in: /10.3892/or.2019.7111
  • Authors:
    • Dehua Tang
    • Lei Xu
    • Mingming Zhang
    • Robert Gregory Dorfman
    • Yida Pan
    • Qian Zhou
    • Lixing Zhou
    • Yuming Wang
    • Yang Li
    • Yuyao Yin
    • Lei Wang
    • Xiaoping Zou
  • View Affiliations / Copyright

    Affiliations: Department of Gastroenterology, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing University, Nanjing, Jiangsu 210008, P.R. China, Department of Gastroenterology, Nanjing Medical University Affiliated Drum Tower Clinical Medical College, Nanjing Medical University, Nanjing, Jiangsu 210008, P.R. China, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA, Department of Digestive Diseases of Huashan Hospital, Fudan University, Shanghai 200040, P.R. China, School of Life Sciences, Fudan University, Shanghai 200032, P.R. China
  • Pages: 1957-1965
    |
    Published online on: February 20, 2018
       https://doi.org/10.3892/or.2018.6275
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Abstract

Cholangiocarcinoma (CCA) is a highly lethal malignancy with an often late diagnosis and consequent poor prognosis. Chemotherapy is the only therapeutic strategy for most patients. Compared to normal cells, tumor cells preferentially metabolize glucose to lactate, even in aerobic conditions. Such metabolic alterations not only support the growth and invasion of tumor cells, but also promote their chemoresistance. The purpose of our study was to explore the role of metformin in regulating the metabolism of CCA, as well as to investigate whether metformin could act as a chemosensitizer of the HDAC3 inhibitor BG45, and therefore have potential for the treatment of CCA. Through bioinformatic analysis, we found that aberrant metabolism contributed to the proliferation of CCA cells. Seahorse XF96 Extracellular Flux Analyzer analysis and lactate production analysis showed that metformin could act as a suppressor of the Warburg effect in CCA cells. Western blotting showed that metformin decreased the expression of LDHA, which plays a key role in the Warburg effect. However, suppression of the Warburg effect was not sufficient to induce CCA cellular apoptosis. According to our previous research, which showed that an HDAC3 inhibitor (MI192) was involved in CCA apoptosis, we observed that metformin combined with BG45 (a novel specific HDAC3 inhibitor) effectively induced the apoptosis of CCA cells in vitro. Furthermore, in vivo experiments revealed that the combined treatment with metformin and BG45 markedly reduced CCA growth in a CCA xenograft model. Our data revealed that reversing the Warburg effect with metformin sensitizes cells to the antitumor effects of HDAC3 inhibitors. This provides a rationale for using the combination of metformin and BG45 as a new therapeutic strategy in the treatment of CCA.
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View References

1 

Razumilava N and Gores GJ: Cholangiocarcinoma. Lancet. 383:2168–2179. 2014. View Article : Google Scholar : PubMed/NCBI

2 

Rizvi S and Gores GJ: Pathogenesis, diagnosis, and management of cholangiocarcinoma. Gastroenterology. 145:1215–1229. 2013. View Article : Google Scholar : PubMed/NCBI

3 

Bridgewater J, Galle PR, Khan SA, Llovet JM, Park JW, Patel T, Pawlik TM and Gores GJ: Guidelines for the diagnosis and management of intrahepatic cholangiocarcinoma. J Hepatol. 60:1268–1289. 2014. View Article : Google Scholar : PubMed/NCBI

4 

Valle JW, Lamarca A, Goyal L, Barriuso J and Zhu AX: New horizons for precision medicine in biliary tract cancers. Cancer Discov. 7:943–962. 2017. View Article : Google Scholar : PubMed/NCBI

5 

Inzucchi SE, Lipska KJ, Mayo H, Bailey CJ and McGuire DK: Metformin in patients with type 2 diabetes and kidney disease: A systematic review. Jama. 312:2668–2675. 2014. View Article : Google Scholar : PubMed/NCBI

6 

Schneider MB, Matsuzaki H, Haorah J, Ulrich A, Standop J, Ding XZ, Adrian TE and Pour PM: Prevention of pancreatic cancer induction in hamsters by metformin. Gastroenterology. 120:1263–1270. 2001. View Article : Google Scholar : PubMed/NCBI

7 

Evans JM, Donnelly LA, Emslie-Smith AM, Alessi DR and Morris AD: Metformin and reduced risk of cancer in diabetic patients. BMJ. 330:1304–1305. 2005. View Article : Google Scholar : PubMed/NCBI

8 

Camacho L, Dasgupta A and Jiralerspong S: Metformin in breast cancer-an evolving mystery. Breast Cancer Res. 17:882015. View Article : Google Scholar : PubMed/NCBI

9 

Ezewuiro O, Grushko TA, Kocherginsky M, Habis M, Hurteau JA, Mills KA, Hunn J, Olopade OI, Fleming GF and Romero IL: Association of Metformin Use with outcomes in advanced endometrial cancer treated with chemotherapy. PLoS One. 11:e01471452016. View Article : Google Scholar : PubMed/NCBI

10 

Griss T, Vincent EE, Egnatchik R, Chen J, Ma EH, Faubert B, Viollet B, DeBerardinis RJ and Jones RG: Metformin antagonizes cancer cell proliferation by suppressing mitochondrial-dependent biosynthesis. PLoS Biol. 13:e10023092015. View Article : Google Scholar : PubMed/NCBI

11 

Ling S, Xie H, Yang F, Shan Q, Dai H, Zhuo J, Wei X, Song P, Zhou L, Xu X and Zheng S: Metformin potentiates the effect of arsenic trioxide suppressing intrahepatic cholangiocarcinoma: Roles of p38 MAPK, ERK3, and mTORC1. J Hematol Oncol. 10:592017. View Article : Google Scholar : PubMed/NCBI

12 

Vander Heiden MG, Cantley LC and Thompson CB: Understanding the Warburg effect: The metabolic requirements of cell proliferation. Science. 324:1029–1033. 2009. View Article : Google Scholar : PubMed/NCBI

13 

Green DR, Galluzzi L and Kroemer G: Cell biology. Metabolic control of cell death. Science. 345:12502562014. View Article : Google Scholar : PubMed/NCBI

14 

Liu X, Romero IL, Litchfield LM, Lengyel E and Locasale JW: Metformin targets central carbon metabolism and reveals mitochondrial requirements in human cancers. Cell Metab. 24:728–739. 2016. View Article : Google Scholar : PubMed/NCBI

15 

Zhijun H, Shusheng W, Han M, Jianping L, Li-sen Q and Dechun L: Pre-clinical characterization of 4SC-202, a novel class I HDAC inhibitor, against colorectal cancer cells. Tumor Biol. 37:10257–10267. 2016. View Article : Google Scholar

16 

Minami J, Suzuki R, Mazitschek R, Gorgun G, Ghosh B, Cirstea D, Hu Y, Mimura N, Ohguchi H, Cottini F, et al: Histone deacetylase 3 as a novel therapeutic target in multiple myeloma. Leukemia. 28:680–689. 2014. View Article : Google Scholar : PubMed/NCBI

17 

Lakshmaiah KC, Jacob LA, Aparna S, Lokanatha D and Saldanha SC: Epigenetic therapy of cancer with histone deacetylase inhibitors. J Cancer Res Ther. 10:469–478. 2014.PubMed/NCBI

18 

Harting K and Knöll B: SIRT2-mediated protein deacetylation: An emerging key regulator in brain physiology and pathology. Eur J Cell Biol. 89:262–269. 2010. View Article : Google Scholar : PubMed/NCBI

19 

Wang LT, Liou JP, Li YH, Liu YM, Pan SL and Teng CM: A novel class I HDAC inhibitor, MPT0G030, induces cell apoptosis and differentiation in human colorectal cancer cells via HDAC1/PKCδ and E-cadherin. Oncotarget. 5:5651–5662. 2014. View Article : Google Scholar : PubMed/NCBI

20 

Yin Y, Zhang M, Dorfman RG, Li Y, Zhao Z, Pan Y, Zhou Q, Huang S, Zhao S, Yao Y and Zou X: Histone deacetylase 3 overexpression in human cholangiocarcinoma and promotion of cell growth via apoptosis inhibition. Cell Death Dis. 8:e28562017. View Article : Google Scholar : PubMed/NCBI

21 

Zhang QL, Wang L, Zhang YW, Jiang XX, Yang F, Wu WL, Janin A, Chen Z, Shen ZX, Chen SJ and Zhao WL: The proteasome inhibitor bortezomib interacts synergistically with the histone deacetylase inhibitor suberoylanilide hydroxamic acid to induce T-leukemia/lymphoma cells apoptosis. Leukemia. 23:1507–1514. 2009. View Article : Google Scholar : PubMed/NCBI

22 

Richon VM, Emiliani S, Verdin E, Webb Y, Breslow R, Rifkind RA and Marks PA: A class of hybrid polar inducers of transformed cell differentiation inhibits histone deacetylases. Proc Natl Acad Sci USA. 95:pp. 3003–3007. 1998; View Article : Google Scholar : PubMed/NCBI

23 

Xiao Y, Wang J, Qin Y, Xuan Y, Jia Y, Hu W, Yu W, Dai M, Li Z, Yi C, et al: Ku80 cooperates with CBP to promote COX-2 expression and tumor growth. Oncotarget. 6:8046–8061. 2015. View Article : Google Scholar : PubMed/NCBI

24 

Shibata T and Aburatani H: Exploration of liver cancer genomes. Nat Rev Gastroenterol Hepatol. 11:340–349. 2014. View Article : Google Scholar : PubMed/NCBI

25 

Alimova IN, Liu B, Fan Z, Edgerton SM, Dillon T, Lind SE and Thor AD: Metformin inhibits breast cancer cell growth, colony formation and induces cell cycle arrest in vitro. Cell Cycle. 8:909–915. 2009. View Article : Google Scholar : PubMed/NCBI

26 

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

27 

Zhou Y, Tozzi F, Chen J, Fan F, Xia L, Wang J, Gao G, Zhang A, Xia X, Brasher H, et al: Intracellular ATP levels are a pivotal determinant of chemoresistance in colon cancer cells. Cancer Res. 72:304–314. 2012. View Article : Google Scholar : PubMed/NCBI

28 

Iliopoulos D, Hirsch HA and Struhl K: Metformin decreases the dose of chemotherapy for prolonging tumor remission in mouse xenografts involving multiple cancer cell types. Cancer Res. 71:3196–3201. 2011. View Article : Google Scholar : PubMed/NCBI

29 

Vander Heiden MG: Targeting cancer metabolism: A therapeutic window opens. Nat Rev Drug Discov. 10:671–684. 2011. View Article : Google Scholar : PubMed/NCBI

30 

Shukla SK, Purohit V, Mehla K, Gunda V, Chaika NV, Vernucci E, King RJ, Abrego J, Goode GD, Dasgupta A, et al: MUC1 and HIF-1alpha signaling crosstalk induces anabolic glucose metabolism to impart gemcitabine resistance to pancreatic cancer. Cancer Cell. 32:71–87.e7. 2017. View Article : Google Scholar : PubMed/NCBI

31 

Herranz D, Ambesi-Impiombato A, Sudderth J, Sánchez-Martín M, Belver L, Tosello V, Xu L, Wendorff AA, Castillo M, Haydu JE, et al: Metabolic reprogramming induces resistance to anti-NOTCH1 therapies in T cell acute lymphoblastic leukemia. Nat Med. 21:1182–1189. 2015. View Article : Google Scholar : PubMed/NCBI

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Copy and paste a formatted citation
Spandidos Publications style
Tang D, Xu L, Zhang M, Dorfman RG, Pan Y, Zhou Q, Zhou L, Wang Y, Li Y, Yin Y, Yin Y, et al: Metformin facilitates BG45‑induced apoptosis via an anti‑Warburg effect in cholangiocarcinoma cells Corrigendum in /10.3892/or.2019.7111. Oncol Rep 39: 1957-1965, 2018.
APA
Tang, D., Xu, L., Zhang, M., Dorfman, R.G., Pan, Y., Zhou, Q. ... Zou, X. (2018). Metformin facilitates BG45‑induced apoptosis via an anti‑Warburg effect in cholangiocarcinoma cells Corrigendum in /10.3892/or.2019.7111. Oncology Reports, 39, 1957-1965. https://doi.org/10.3892/or.2018.6275
MLA
Tang, D., Xu, L., Zhang, M., Dorfman, R. G., Pan, Y., Zhou, Q., Zhou, L., Wang, Y., Li, Y., Yin, Y., Wang, L., Zou, X."Metformin facilitates BG45‑induced apoptosis via an anti‑Warburg effect in cholangiocarcinoma cells Corrigendum in /10.3892/or.2019.7111". Oncology Reports 39.4 (2018): 1957-1965.
Chicago
Tang, D., Xu, L., Zhang, M., Dorfman, R. G., Pan, Y., Zhou, Q., Zhou, L., Wang, Y., Li, Y., Yin, Y., Wang, L., Zou, X."Metformin facilitates BG45‑induced apoptosis via an anti‑Warburg effect in cholangiocarcinoma cells Corrigendum in /10.3892/or.2019.7111". Oncology Reports 39, no. 4 (2018): 1957-1965. https://doi.org/10.3892/or.2018.6275
Copy and paste a formatted citation
x
Spandidos Publications style
Tang D, Xu L, Zhang M, Dorfman RG, Pan Y, Zhou Q, Zhou L, Wang Y, Li Y, Yin Y, Yin Y, et al: Metformin facilitates BG45‑induced apoptosis via an anti‑Warburg effect in cholangiocarcinoma cells Corrigendum in /10.3892/or.2019.7111. Oncol Rep 39: 1957-1965, 2018.
APA
Tang, D., Xu, L., Zhang, M., Dorfman, R.G., Pan, Y., Zhou, Q. ... Zou, X. (2018). Metformin facilitates BG45‑induced apoptosis via an anti‑Warburg effect in cholangiocarcinoma cells Corrigendum in /10.3892/or.2019.7111. Oncology Reports, 39, 1957-1965. https://doi.org/10.3892/or.2018.6275
MLA
Tang, D., Xu, L., Zhang, M., Dorfman, R. G., Pan, Y., Zhou, Q., Zhou, L., Wang, Y., Li, Y., Yin, Y., Wang, L., Zou, X."Metformin facilitates BG45‑induced apoptosis via an anti‑Warburg effect in cholangiocarcinoma cells Corrigendum in /10.3892/or.2019.7111". Oncology Reports 39.4 (2018): 1957-1965.
Chicago
Tang, D., Xu, L., Zhang, M., Dorfman, R. G., Pan, Y., Zhou, Q., Zhou, L., Wang, Y., Li, Y., Yin, Y., Wang, L., Zou, X."Metformin facilitates BG45‑induced apoptosis via an anti‑Warburg effect in cholangiocarcinoma cells Corrigendum in /10.3892/or.2019.7111". Oncology Reports 39, no. 4 (2018): 1957-1965. https://doi.org/10.3892/or.2018.6275
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