Adv Pharm Bull. 2020;10(3): 458-463.
doi: 10.34172/apb.2020.056
  Abstract View: 54
  PDF Download: 42

Research Article

Activation of PPARγ Inhibits TLR4 Signal Transduction Pathway in Melanoma Cancer in Vitro

Nasim Dana 1 ORCID logo, Golnaz Vaseghi 2,1 ORCID logo, Shaghayegh Haghjooy Javanmard 1 * ORCID logo

1 Applied Physiology Research Center, Cardiovascular Research Institute, Isfahan University of Medical sciences, Isfahan, Iran.
2 Isfahan Cardiovascular Research Center, Cardiovascular Research Institute, Isfahan University of Medical sciences, Isfahan, Iran.


Purpose: Although peroxisome proliferator-activated receptor γ (PPARγ) is known as a regulatorof fatty acid storage, fat cell differentiation, glucose and lipid metabolism, recent studiesshow that PPARγ has anticancer effects. The mechanisms of PPARγ activation in melanomacancer remain unclarified. Recently, increased TLR4 expression has been associated with themelanoma cancer progression. We investigated whether the anti-cancer effect of PPARγ isthrough regulating TLR4 signaling pathway.Methods: Mouse melanoma cells (B16F10) were treated in different groups: control, pioglitazone(1, 10, 100, 300 μmol/L), lipopolysaccharide (LPS) (5 μg/mL) and LPS + pioglitazone. In anotherexperiment, they were treated with CLI-095 (1 μM), and after 1 hour pioglitazone was addedand subsequently stimulated with LPS. MTT assay was performed to measure the cell viabilityin vitro. The expression of Tlr4, Myd88, Nf-κb genes were evaluated by quantitative reversetranscription PCR (qRT-PCR) in different groups. The concentration of tumor necrosis factoralpha and Interleukin 1 beta in the cell culture medium were measured by enzyme-linkedimmunosorbent assay (ELISA) kits.Results: We show that activation of PPARγ by its agonist, pioglitazone, reduces cell proliferation,Tlr-4, Myd-88, Nf-kb mRNA expression, and tumor necrosis factor-alpha (TNF-α) productionbut not interleukin-1 β (IL-1β) in B16F10 LPS–stimulated cells in vitro. Moreover, treatment ofB16F10 cells with TLR4 inhibitor prior treatment with pioglitazone indicate that the anticancereffects of pioglitazone on melanoma cells was dependent on TLR4.Conclusion: The results indicate that pioglitazone has a beneficial protective effect againstmelanoma by affecting the TLR4 signaling pathway.
Keywords: Peroxisome proliferatoractivated receptor, Toll-like receptor 4, Melanoma, Pioglitazone
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Submitted: 06 May 2019
Revision: 30 Dec 2019
Accepted: 23 Jan 2020
ePublished: 11 May 2020
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