The effect of fenofibrate, a PPARα activator on toll-like receptor-4 signal transduction in melanoma both in vitro and in vivo
The effect of fenofibrate, a PPARα activator on toll-like receptor-4 signal transduction in melanoma both in vitro and in vivo
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DOI：
10.1007/s12094-019-02150-7
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发表时间：
2020-04-01
影响因子：
3.4
通讯作者：
Vaseghi, G.
中科院分区：
文献类型：
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作者：
Dana, N.;Javanmard, S. Haghjooy;Vaseghi, G.
背景过氧化物酶体增殖激活受体(PPAR) α配体对黑色素瘤细胞生长和转移潜能的抗癌作用已被证实。然而，这些影响的机制仍有待阐明。在这里，我们研究了非诺贝特（PPAR配体）对小鼠黑色素瘤中toll样受体-4 （TLR-4）信号传导的影响。方法用非诺贝特、LPS或LPS +非诺贝特或TLR4抑制剂cl -095预处理小鼠黑色素瘤细胞（B16F10），再用非诺贝特预处理。在体内模型中，C57BL/6小鼠皮下注射B16F10细胞（预处理/不预处理），在可触及肿瘤发生后给予非诺贝特。检测细胞增殖、Tlr4、Myd88、Nf-kappa b1基因表达水平、TLR-4蛋白表达、tnf - α水平及肿瘤体积。结果非诺贝特显著抑制lps刺激的B16F10细胞Tlr-4、Myd-88和Nf-kb1 mRNA表达和tnf - α浓度。此外，阻断TLR-4信号通路可增加非诺贝特的抗炎潜能。非诺贝特还能降低lps诱导的肿瘤体积，降低肿瘤组织中Tlr-4、Myd-88、Nf-kb1 mRNA和Tlr-4蛋白的表达，降低肿瘤组织裂解液中tnf - α的水平。结论非诺贝特可能通过与tlr4依赖性信号通路（TLR-4/MyD-88/ NF-kB）相互作用发挥抗黑素瘤作用。
Background The anti-cancer effect of peroxisome proliferator-activated receptor (PPAR) alpha 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-kappa b1 genes, TLR-4 protein expression, TNF-alpha 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-alpha 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-alpha 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).