Advertisement

The effect of fenofibrate, a PPARα activator on toll-like receptor-4 signal transduction in melanoma both in vitro and in vivo

  • N. Dana
  • S. Haghjooy Javanmard
  • G. VaseghiEmail author
Research Article

Abstract

Background

The anti-cancer effect of peroxisome proliferator-activated receptor (PPAR) α ligands on growth and metastatic potential of melanoma cells has been shown previously. However, the mechanism underlying these effects remains to be elucidated. Here, we investigated the effects of fenofibrate (PPAR ligand) on Toll-like receptor-4 (TLR-4) signaling in mice melanoma.

Methods

Mice melanoma cells (B16F10) were treated with fenofibrate or LPS or LPS + fenofibrate or pre-treated with CLI-095 (a TLR4 inhibitor), followed by fenofibrate. In in vivo model, C57BL/6 mice were subcutaneously injected with B16F10 cells (with/without LPS pre-treatment), and fenofibrate was administrated after development of palpable tumors. Cell proliferation, the expression level of Tlr4, Myd88, Nf-κb1 genes, TLR-4 protein expression, TNF-α levels, and tumor volume were measured.

Result

Our results indicated that fenofibrate significantly inhibited the Tlr-4, Myd-88, and Nf-kb1 mRNA expression and TNF-α concentration in B16F10 LPS-stimulated cells. In addition, blocking TLR-4 signaling increased the anti-inflammatory potential of fenofibrate. Also fenofibrate can reduce LPS-induced tumor volume, Tlr-4, Myd-88, Nf-kb1 mRNA, and TLR-4 protein expression in tumor tissue and also TNF-α level in tumor tissue lysate.

Conclusion

Our data indicate that fenofibrate may exert its anti-melanoma effects via interaction with TLR4-dependent signaling pathway (TLR-4/MyD-88/ NF-kB).

Keywords

PPAR alpha Toll-like receptor-4 Melanoma 

Notes

Funding

This article was derived from a PhD thesis promoted at Isfahan University of Medical Sciences with Grant number of No. 394617. This work was financially supported by Iran National Science Foundation (INSF) [Grant no. 95844116].

Compliance with ethical standards

Conflict of interest

The author(s) declare that they have no conflict of interest.

Ethics approval

The animals were cared for in accordance with the principles and guidelines of the Canadian Council on Animal Care and the use of animals was reviewed and approved by the appropriate animal care review committee at the Ethics Committee of Isfahan University (approval ID: IR. MUI. REC.1394.3.617).

Informed consent

The research did not involve human participants.

References

  1. 1.
    Wilking MJ, Singh C, Nihal M, Zhong W, Ahmad N. SIRT1 deacetylase is overexpressed in human melanoma and its small molecule inhibition imparts anti-proliferative response via p53 activation. Arch Biochem Biophys. 2014;563:94–100.CrossRefGoogle Scholar
  2. 2.
    Mhaidat NM, Zhang XD, Allen J, Avery-Kiejda KA, Scott RJ, Hersey P. Temozolomide induces senescence but not apoptosis in human melanoma cells. Br J Cancer. 2007;97:1225–333.CrossRefGoogle Scholar
  3. 3.
    Hawryluk EB, Tsao H. Melanoma: clinical features and genomic insights. Cold Spring Harbor Perspect Med. 2014;4:a015388.CrossRefGoogle Scholar
  4. 4.
    Jin SH, Kang HY. Activation of toll-like receptors 1, 2, 4, 5, and 7 on human melanocytes modulate pigmentation. Ann Dermatol. 2010;22:486.CrossRefGoogle Scholar
  5. 5.
    Beutler BA. TLRs and innate immunity. Blood. 2009;113:1399–407.CrossRefGoogle Scholar
  6. 6.
    Ji Y-Y, Liu J-T, Liu N, Wang Z-D, Liu C-H. PPARalpha activator fenofibrate modulates angiotensin II-induced inflammatory responses in vascular smooth muscle cells via the TLR4-dependent signaling pathway. Biochem Pharmacol. 2009;78:1186–97.CrossRefGoogle Scholar
  7. 7.
    Fukata M, Hernandez Y, Conduah D, Cohen J, Chen A, Breglio K, et al. Innate immune signaling by Toll-like receptor-4 (TLR4) shapes the inflammatory microenvironment in colitis-associated tumors. Inflamm Bowel Dis. 2009;15:997–1006.CrossRefGoogle Scholar
  8. 8.
    Multhoff G, Molls M, Radons J. Chronic inflammation in cancer development. Front Immunol. 2011;2:98.Google Scholar
  9. 9.
    Grabacka M, Pierzchalska M, Reiss K. Peroxisome proliferator activated receptor α ligands as anticancer drugs targeting mitochondrial metabolism. Curr Pharm Biotechnol. 2013;14:342–56.CrossRefGoogle Scholar
  10. 10.
    Li T, Zhang Q, Zhang J, Yang G, Shao Z, Luo J, et al. Fenofibrate induces apoptosis of triple-negative breast cancer cells via activation of NF-κB pathway. BMC Cancer. 2014;14:96.CrossRefGoogle Scholar
  11. 11.
    Panigrahy D, Kaipainen A, Huang S, Butterfield CE, Barnés CM, Fannon M, et al. PPARalpha agonist fenofibrate suppresses tumor growth through direct and indirect angiogenesis inhibition. Proc Natl Acad Sci USA. 2008;105:985–90.CrossRefGoogle Scholar
  12. 12.
    Koltai T. Fenofibrate in cancer: mechanisms involved in anticancer activity. F1000Research. 2015. https://f1000research.com/articles/4-55/v2
  13. 13.
    Appel S, Mirakaj V, Bringmann A, Weck MM, Grünebach F, Brossart P. PPAR-gamma agonists inhibit toll-like receptor-mediated activation of dendritic cells via the MAP kinase and NF-kappaB pathways. Blood. 2005;106:3888–944.CrossRefGoogle Scholar
  14. 14.
    Sun H, Zhu X, Cai W, Qiu L. Hypaphorine attenuates lipopolysaccharide-induced endothelial inflammation via regulation of TLR4 and PPAR-γ dependent on PI3K/Akt/mTOR signal pathway. Int J Mol Sci. 2017;18:844.CrossRefGoogle Scholar
  15. 15.
    Zhao W, Wang L, Zhang M, Wang P, Zhang L, Yuan C, et al. Peroxisome proliferator-activated receptor gamma negatively regulates IFN-beta production in Toll-like receptor (TLR) 3- and TLR4-stimulated macrophages by preventing interferon regulatory factor 3 binding to the IFN-beta promoter. J Biol Chem. 2011;286:5519–28.CrossRefGoogle Scholar
  16. 16.
    Overwijk WW, Restifo NP. B16 as a mouse model for human melanoma. Curr Protoc Immunol. 2001;39:21–21 (Chapter 20: Unit 20.1).Google Scholar
  17. 17.
    Dana N, Javanmard SH, Vaseghi G. Effect of lipopolysaccharide on toll-like receptor-4 signals in mouse cancer cells. Bratisl Lek Listy. 2017;118:598–601.Google Scholar
  18. 18.
    Jensen MM, Jørgensen JT, Binderup T, Kjaer A. Tumor volume in subcutaneous mouse xenografts measured by microCT is more accurate and reproducible than determined by 18F-FDG-microPET or external caliper. BMC Med Imaging. 2008;8:16.CrossRefGoogle Scholar
  19. 19.
    Xia S, Lin R, Jin L, Zhao L, Kang H-B, Pan Y, et al. Prevention of dietary-fat-fueled ketogenesis attenuates BRAF V600E tumor growth. Cell Metab. 2017;25:358–73.CrossRefGoogle Scholar
  20. 20.
    Grabacka MM, Wilk A, Antonczyk A, Banks P, Walczyk-Tytko E, Dean M, et al. Fenofibrate induces ketone body production in melanoma and glioblastoma cells. Front Endocrinol. 2016;7:5.CrossRefGoogle Scholar
  21. 21.
    Szlosarek PW, Balkwill FR. Tumour necrosis factor alpha: a potential target for the therapy of solid tumours. Lancet Oncol. 2003;4:565–73.CrossRefGoogle Scholar
  22. 22.
    Naldini A, Carraro F. Role of inflammatory mediators in angiogenesis. Curr Drug Targets Inflamm Allergy. 2005;4:3–8.CrossRefGoogle Scholar
  23. 23.
    Pollard JW. Tumour-educated macrophages promote tumour progression and metastasis. Nat Rev Cancer. 2004;4:71–8.CrossRefGoogle Scholar
  24. 24.
    Balkwill F. Tumor necrosis factor or tumor promoting factor? Cytokine Growth Factor Rev. 2002;13:135–41.CrossRefGoogle Scholar
  25. 25.
    Ding J-L, Zhou Z-G, Zhou X-Y, Zhou B, Wang L, Wang R, et al. Attenuation of acute pancreatitis by peroxisome proliferator-activated receptor-α in rats: the effect on Toll-like receptor signaling pathways. Pancreas. 2013;42:114–22.CrossRefGoogle Scholar

Copyright information

© Federación de Sociedades Españolas de Oncología (FESEO) 2019

Authors and Affiliations

  1. 1.Applied Physiology Research Center and Department of Physiology, Cardiovascular Research InstituteIsfahan University of Medical SciencesIsfahanIran
  2. 2.Isfahan Cardiovascular Research Center, Cardiovascular Research InstituteIsfahan University of Medical SciencesIsfahanIran

Personalised recommendations