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The obeticholic acid can positively regulate the cancerous behavior of MCF7 breast cancer cell line

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Abstract

Background

The diagnosis and treatment processes of cancer are among the main challenges of medical science in recent decades. The use of different therapeutic agents is one of the most common methods frequently utilized for cancer treatment. Accumulating evidence points to a potential effect of Obeticholic acid (OCA), a specific ligand for farnesoid X receptor, on the regulation of cancer-associated pathways. In spite of tremendous efforts to introduce OCA into the clinical setting, there is a great deal of uncertainty about its impact on breast cancer treatment. This study was performed to evaluate the effects of OCA on breast cancer.

Methods and results

In this experiment, the MCF-7 (Michigan Cancer Foundation-7) cell line was treated with 0.1 µM OCA, and cancerous characteristics of the MCF-7 cell line was evaluated by the MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-2 H-tetrazolium bromide) assay, gelatin zymography, western blot, Real-time PCR, flow cytometry, and ELISA techniques. The results indicated that OCA increased the rate of apoptosis and the expression levels of PPARα (Peroxisome proliferator-activated receptor alpha) and TIMP-1 (tissue inhibitor of metalloproteinase-1) genes in this cell line, while it reduced the mRNA levels of MMP7 (matrix metalloproteinase 7) and Bcl-2 (B-cell lymphoma 2) genes, as well as the protein levels of the active form of AKT (protein kinase B), Erk1/2 (extracellular signal-regulated kinase 1/2) and STAT3 (Signal transducers and activators of transcription-3). Also, OCA decreased the activity of MMP9, while it increased the secretion of VEGF-A (vascular endothelial growth factor-A).

Conclusions

It seems that OCA can exert anti-cancer effects on the MCF-7 cells by reducing growth, proliferation, migration, invasion, and regulation of the expression of genes involved in cancer-associated pathways. However, it should be noted that further studies are warranted to establish this concept, especially the increase of VEGF-A can be considered a challenge for the results of this study.

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Data availability

The datasets generated during and/or analysed during the current study are available from the corresponding author on reasonable request.

Abbreviations

FXR:

Farnesoid X receptor

OCA:

Obeticholic acid

MCF7:

Michigan cancer foundation-7

SHP:

Small heterodimer partner

Bcl-2:

B-cell lymphoma 2

Bid:

BH3 interacting domain death agonist

Bcl-xL:

B-cell lymphoma-extra large

STAT3:

Signal transducers and activators of transcription 3

AMPK:

AMP-activated protein kinase

AKT:

Protein kinase B

mTORC1:

Mammalian target of rapamycin complex 1

PPARα:

Peroxisome proliferator-activated receptor alpha

Erk1/2:

Extracellular signal-regulated kinase 1/2

TIMP-1:

Tissue inhibitor of metalloproteinase-1

MMP:

Matrix metalloproteinase

VEGF:

Vascular endothelial growth factor

TGR5:

Takeda G-protein-coupled receptor 5

VDR:

Vitamin D receptor

CDCA:

Chenodeoxycholic acid

FDA:

Food and drug administration

DMED:

Dulbecco’s modified eagle medium

FBS:

Fetal bovine serum

PBS:

Phosphate-buffered saline

FAS:

Fatty acid synthase

ACC:

Acetyl-CoA carboxylase

CPT-1:

Carnitine palmitoyltransferase I

LCA:

Lithocholic acid

TUDCA:

Tauroursodeoxycholic acid

UDCA:

Ursodeoxycholic acid

DCA:

Deoxycholic acid

References

  1. Arnold M, Morgan E, Rumgay H, Mafra A, Singh D, Laversanne M, Vignat J, Gralow JR, Cardoso F, Siesling S (2022) Current and future burden of breast cancer: global statistics for 2020 and 2040. Breast 66:15–23. https://doi.org/10.1016/j.breast.2022.08.010

    Article  PubMed  PubMed Central  Google Scholar 

  2. Shi H, Ji H, Zhu F, Zhao Y, Yin Y, Shu F, Wang L (2022) Antitumor potential of peptides isolated from brucea javanica globulin fraction on MCF-7 cells. Pharmacogn Mag. https://doi.org/10.4103/pm.pm_540_21

    Article  Google Scholar 

  3. Wu J, Nagy LE, Wang L (2021) The long and the small collide: LncRNAs and small heterodimer partner (SHP) in liver disease. Mol Cell Endocrinol 528:111262

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Nguyen J, Riessen R, Rodriguez-Otero J, Anakk S (2020) Investigating the intestine-specific role of small heterodimer partner. FASEB J 34(S1):1–1. https://doi.org/10.1096/fasebj.2020.34.s1.00657

    Article  Google Scholar 

  5. Chen S, Sun S, Feng Y, Li X, Yin G, Liang P, Yu W, Meng D, Zhang X, Liu H (2023) Diosgenin attenuates nonalcoholic hepatic steatosis through the hepatic FXR-SHP-SREBP1C/PPARα/CD36 pathway. Eur J Pharmacol. https://doi.org/10.1016/j.ejphar.2023.175808

    Article  PubMed  Google Scholar 

  6. Lee YJ, Lee E-Y, Choi BH, Jang H, Myung J-K, You HJ (2020) The role of nuclear receptor subfamily 1 group H member 4 (NR1H4) in colon cancer cell survival through the regulation of c-Myc stability. Mol Cells 43(5):459–468. https://doi.org/10.14348/molcells.2020.0041

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Alasmael N, Mohan R, Meira LB, Swales KE, Plant NJ (2016) Activation of the farnesoid X-receptor in breast cancer cell lines results in cytotoxicity but not increased migration potential. Cancer Lett 370(2):250–259. https://doi.org/10.1016/j.canlet.2015.10.031

    Article  CAS  PubMed  Google Scholar 

  8. Yu J, Li S, Guo J, Xu Z, Zheng J, Sun X (2020) Farnesoid X receptor antagonizes Wnt/β-catenin signaling in colorectal tumorigenesis. Cell Death Dis. https://doi.org/10.1038/s41419-020-02819-w

    Article  PubMed  PubMed Central  Google Scholar 

  9. Lai C-R, Wang H-H, Chang H-H, Tsai Y-L, Tsai W-C, Lee C-R, Changchien C-Y, Cheng Y-C, Wu S-TC (2022) Enhancement of farnesoid X receptor inhibits migration, adhesion and angiogenesis through proteasome degradation and VEGF reduction in bladder cancers. Int J Mol Sci 23(9):5259. https://doi.org/10.3390/ijms23095259

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Fiorucci S, Distrutti E (2019) The pharmacology of bile acids and their receptors. Bile Acids Recept. https://doi.org/10.1007/164_2019_238

    Article  Google Scholar 

  11. Moris D, Giaginis C, Tsourouflis G, Theocharis S (2017) Farnesoid-X receptor (FXR) as a promising pharmaceutical target in atherosclerosis. Curr Med Chem 24(11):1147–1157. https://doi.org/10.2174/0929867324666170124151940

    Article  CAS  PubMed  Google Scholar 

  12. Fiorucci S, Biagioli M, Baldoni M, Ricci P, Sepe V, Zampella A, Distrutti E (2021) The identification of farnesoid X receptor modulators as treatment options for nonalcoholic fatty liver disease. Expert Opin Drug Discov 16(10):1193–1208. https://doi.org/10.1080/17460441.2021.1916465

    Article  CAS  PubMed  Google Scholar 

  13. Jiang L, Zhang H, Xiao D, Wei H, Chen Y (2021) Farnesoid X receptor (FXR): structures and ligands. Comput Struct Biotechnol J 19:2148–2159. https://doi.org/10.1016/j.csbj.2021.04.029

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Yang Z, Wang L (2023) Current, emerging, and potential therapies for non-alcoholic steatohepatitis. Front Pharmacol 14:1152042. https://doi.org/10.3389/fphar.2023.1152042

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Floreani A, Gabbia D, De Martin S (2022) Obeticholic acid for primary biliary cholangitis. Biomedicines 10(10):2464. https://doi.org/10.3390/biomedicines10102464

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Mao JJ, Pillai GG, Andrade CJ, Ligibel JA, Basu P, Cohen L, Khan IA, Mustian KM, Puthiyedath R, Dhiman KS (2022) Integrative oncology: addressing the global challenges of cancer prevention and treatment. CA: Cancer J Clin 72(2):144–164. https://doi.org/10.3322/caac.21706

    Article  PubMed  Google Scholar 

  17. Aishwarya TS, Mounika N, Vishwakarma G, Adela R (2022) Effect of obeticholic acid in non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH) patients: a systematic review and meta-analysis. RPS Pharm Pharmacol Rep. https://doi.org/10.1093/rpsppr/rqac001

    Article  Google Scholar 

  18. Atanasova VS, Riedl A, Strobl M, Flandorfer J, Unterleuthner D, Weindorfer C, Neuhold P, Stang S, Hengstschläger M, Bergmann M (2023) Selective eradication of colon cancer cells harboring PI3K and/or MAPK pathway mutations in 3D culture by combined PI3K/AKT/mTOR pathway and MEK inhibition. Int J Mol Sci. https://doi.org/10.3390/ijms24021668

    Article  PubMed  PubMed Central  Google Scholar 

  19. Amable G, Martínez-León E, Picco ME, Di Siervi N, Davio C, Rozengurt E, Rey O (2019) Metformin inhibits β-catenin phosphorylation on Ser-552 through an AMPK/PI3K/Akt pathway in colorectal cancer cells. Int J Biochem Cell Biol 112:88–94. https://doi.org/10.1016/j.biocel.2019.05.004

    Article  CAS  PubMed  Google Scholar 

  20. Fan X, Xie M, Zhao F, Li J, Fan C, Zheng H, Wei Z, Ci X, Zhang S (2021) Daphnetin triggers ROS-induced cell death and induces cytoprotective autophagy by modulating the AMPK/Akt/mTOR pathway in ovarian cancer. Phytomedicine 82:153465. https://doi.org/10.1016/j.phymed.2021.153465

    Article  CAS  PubMed  Google Scholar 

  21. Chen Y-H, Yang S-F, Yang C-K, Tsai H-D, Chen T-H, Chou M-CH (2021) Metformin induces apoptosis and inhibits migration by activating the AMPK/p53 axis and suppressing PI3K/AKT signaling in human cervical cancer cells. Mol Med Rep 23(1):1–1. https://doi.org/10.3892/mmr.2020.11725

    Article  CAS  Google Scholar 

  22. Xiao J-B, Ma J-Q, Yakefu K, Tursun M (2020) Effect of the SIRT3-AMPK/PPAR pathway on invasion and migration of cervical cancer cells. Int J Clin Exp Pathol 13(10):2495. https://doi.org/10.1016/j.yexcr.2018.01.036

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Yaguchi T, Taira H, Kameno M, Kawakami J (2022) Mitochondrial dynamics of Bcl-2 family during E2-induced apoptosis correlates with the malignant of endometrial. Journal Cancer Cells. https://doi.org/10.21203/rs.3.rs-1260502/v1

    Article  Google Scholar 

  24. Qin D, Wang R, Ji J, Wang D, Lu Y, Cao S, Chen Y, Wang L, Chen X, Zhang L (2023) Hepatocyte-specific Sox9 knockout ameliorates acute liver injury by suppressing SHP signaling and improving mitochondrial function. Cell Biosci 13(1):159. https://doi.org/10.1186/s13578-023-01104-5

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Ozdemir K, Zengin I, Guney Eskiler G, Kocer HB, Ozkan AD, Demiray T, Sahin EO (2022) The predictive role of MMP-2, MMP-9, TIMP-1 and TIMP-2 serum levels in the complete response of the tumor to chemotherapy in breast cancer patients. J Invest Surg 35(7):1544–1550. https://doi.org/10.1080/08941939.2022.2080308

    Article  PubMed  Google Scholar 

  26. Jung HW, Hwang JH (2021) Anticancer effects of Ursi Fel extract and its active compound, ursodeoxycholic acid, in FRO anaplastic thyroid cancer cells. Molecules 26(17):5309. https://doi.org/10.3390/molecules26175309

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Burnat G, Rau T, Elshimi E, Hahn EG, Konturek PC (2007) Bile acids induce overexpression of homeobox gene CDX-2 and vascular endothelial growth factor (VEGF) in human Barrett’s esophageal mucosa and adenocarcinoma cell line. Scand J Gastroenterol 42(12):1460–1465. https://doi.org/10.1080/00365520701452209

    Article  CAS  PubMed  Google Scholar 

  28. Soma T, Kaganoi J, Kawabe A, Kondo K, Tsunoda S, Imamura M, Shimada Y (2006) Chenodeoxycholic acid stimulates the progression of human esophageal cancer cells: a possible mechanism of angiogenesis in patients with esophageal cancer. Int J Cancer 119(4):771–782. https://doi.org/10.1080/00365520701452209

    Article  CAS  PubMed  Google Scholar 

  29. Luu TH, Bard J-M, Carbonnelle D, Chaillou C, Huvelin J-M, Bobin-Dubigeon C, Nazih H (2018) Lithocholic bile acid inhibits lipogenesis and induces apoptosis in breast cancer cells. Cell Oncol 41:13–24. https://doi.org/10.1007/s13402-017-0353-5

    Article  CAS  Google Scholar 

  30. Park GY, Han YK, Han JY, Lee CG (2016) Tauroursodeoxycholic acid reduces the invasion of MDA-MB-231 cells by modulating matrix metalloproteinases 7 and 13. Oncol Lett 12(3):2227–2231. https://doi.org/10.3892/ol.2016.4842

    Article  CAS  PubMed  PubMed Central  ADS  Google Scholar 

  31. Barone I, Vircillo V, Giordano C, Gelsomino L, Győrffy B, Tarallo R, Rinaldi A, Bruno G, Caruso A, Romeo F (2018) Activation of farnesoid X receptor impairs the tumor-promoting function of breast cancer-associated fibroblasts. Cancer Lett 437:89–99. https://doi.org/10.1016/j.canlet.2018.08.026

    Article  CAS  PubMed  Google Scholar 

  32. Giordano C, Barone I, Vircillo V, Panza S, Malivindi R, Gelsomino L, Pellegrino M, Rago V, Mauro L, Lanzino M (2016) Activated FXR inhibits leptin signaling and counteracts tumor-promoting activities of cancer-associated fibroblasts in breast malignancy. Sci Rep 6(1):1–13. https://doi.org/10.1038/srep21782

    Article  CAS  Google Scholar 

  33. Lun W, Yan Q, Guo X, Zhou M, Bai Y, He J, Cao H, Che Q, Guo J, Su Z (2023) Mechanism of action of the bile acid receptor TGR5 in obesity. Acta Pharm Sin B. https://doi.org/10.1016/j.apsb.2023.11.011

    Article  Google Scholar 

  34. Yu J, Lo J-L, Huang L, Zhao A, Metzger E, Adams A, Meinke PT, Wright SD, Cui J (2002) Lithocholic acid decreases expression of bile salt export pump through farnesoid X receptor antagonist activity. J Biol Chem 277(35):31441–31447. https://doi.org/10.1074/jbc.M200474200

    Article  CAS  PubMed  Google Scholar 

  35. Zhang Y, Gao X, Gao S, Liu Y, Wang W, Feng Y, Pei L, Sun Z, Liu L, Wang C (2023) Effect of gut flora mediated-bile acid metabolism on intestinal immune microenvironment. Immunology. https://doi.org/10.1111/imm.13672

    Article  PubMed  PubMed Central  Google Scholar 

  36. Girisa S, Henamayee S, Parama D, Rana V, Dutta U, Kunnumakkara AB (2021) Targeting farnesoid X receptor (FXR) for developing novel therapeutics against cancer. Mol Biomed 2:1–23. https://doi.org/10.1186/s43556-021-00035-2

    Article  Google Scholar 

  37. Ng CH, Tang ASP, Xiao J, Wong ZY, Yong JN, Fu CE, Zeng RW, Tan C, Wong GHZ, Teng M (2023) Safety and tolerability of obeticholic acid in chronic liver disease: a pooled analysis of 1878 individuals. Hepatol Commun. https://doi.org/10.1097/HC9.0000000000000005

    Article  PubMed  PubMed Central  Google Scholar 

  38. Markham A, Keam SJ (2016) Obeticholic acid: first global approval. Drugs 76:1221–1226. https://doi.org/10.1007/s40265-016-0616-x

    Article  CAS  PubMed  Google Scholar 

  39. Abbas SN, Jones D, Kallis Y, Maher L, Patanwala I (2021) Primary biliary cholangitis: assessment and management strategies. Gastrointest Nurs 19(4):S1–S24

    Article  Google Scholar 

  40. Wang K, Zhang Y, Wang G, Hao H, Wang H (2023) FXR agonists for MASH therapy: lessons and perspectives from obeticholic acid. Med Res Rev. https://doi.org/10.1002/med.21991

    Article  PubMed  Google Scholar 

  41. Meshanni JA, Lee JM, Vayas KN, Sun R, Jiang C, Guo GL, Gow AJ, Laskin JD, Laskin DL (2023) Suppression of lung oxidative stress, inflammation and fibrosis following nitrogen mustard exposure by the selective farnesoid X receptor agonist obeticholic acid. J Pharmacol Exp Ther. https://doi.org/10.1124/jpet.123.001557

    Article  Google Scholar 

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Acknowledgements

We would like to acknowledge the Tehran University of Medical Sciences. The present article is extracted from the Ph.D thesis of the author Reza Rahmani, number 9611184002.

Funding

This work was supported by Tehran University of Medical Sciences (Grant Numbers [99-2-410-49563]). Author Maliheh Paknejad has received research support from Tehran University of Medical Sciences.

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Authors and Affiliations

  1. Department of Clinical Biochemistry, Faculty of Medicine, Tehran University of medical sciences, Tehran, Iran

    Reza Rahmani, Neda Eivazi, Solaleh Emamgholipour, Mahdi Aminian & Maliheh Paknejad

  2. Metabolic Disorders Research Center, Endocrinology and Metabolism Molecular-Cellular Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran

    Solaleh Emamgholipour

  3. Department of plant secondary metabolites, Agricultural Biotechnology Research Institute of Iran-Isfahan Branch, Agricultural Research, Education and Extension Organization (AREEO), Isfahan, Iran

    Ali Jalilian

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  1. Reza Rahmani
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Contributions

Conceptualization: RR, AJ, MP. Data curation: RR, SE. Formal analysis: RR, NE. Funding acquisition: MP. Investigation: RR, NE, SE, MA, MP. Methodology: RR, NE, SE, AJ, MP. Project administration: MA, MP. Resources: AJ, MP. Supervision: MA, MP. Visualization: RR, MA, MP. Validation: SE, MA, MP. Writing–original draft: RR, NE. Writing–review & editing: SE, MP.

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Correspondence to Maliheh Paknejad.

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The Tehran University of Medical Sciences Research Ethics Committee has confirmed that no ethical approval is required.

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Rahmani, R., Eivazi, N., Emamgholipour, S. et al. The obeticholic acid can positively regulate the cancerous behavior of MCF7 breast cancer cell line. Mol Biol Rep 51, 250 (2024). https://doi.org/10.1007/s11033-023-09106-9

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