The effect of fenofibrate, a PPARα activator on toll-like receptor-4 signal transduction in melanoma both in vitro and in vivo
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.
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.
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.
Our data indicate that fenofibrate may exert its anti-melanoma effects via interaction with TLR4-dependent signaling pathway (TLR-4/MyD-88/ NF-kB).
KeywordsPPAR alpha Toll-like receptor-4 Melanoma
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.
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).
The research did not involve human participants.
- 8.Multhoff G, Molls M, Radons J. Chronic inflammation in cancer development. Front Immunol. 2011;2:98.Google Scholar
- 12.Koltai T. Fenofibrate in cancer: mechanisms involved in anticancer activity. F1000Research. 2015. https://f1000research.com/articles/4-55/v2
- 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.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.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