Adv Pharm Bull. 2020;10(3): 458-463.
doi: 10.34172/apb.2020.056
PMID: 32665906
PMCID: PMC7335991
Scopus ID: 85088612515
  Abstract View: 466
  PDF Download: 326
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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.
*Corresponding Author: Shaghayegh Haghjooy Javanmard, Tel/Fax: +98 313 6692836, Email: shaghayegh.haghjoo@gmail.com, sh_haghjoo@ med.mui.ac.ir


Purpose: Although peroxisome proliferator-activated receptor γ (PPARγ) is known as a regulator of fatty acid storage, fat cell differentiation, glucose and lipid metabolism, recent studies show that PPARγ has anticancer effects. The mechanisms of PPARγ activation in melanoma cancer remain unclarified. Recently, increased TLR4 expression has been associated with the melanoma cancer progression. We investigated whether the anti-cancer effect of PPARγ is through 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 another experiment, they were treated with CLI-095 (1 μM), and after 1 hour pioglitazone was added and subsequently stimulated with LPS. MTT assay was performed to measure the cell viability in vitro. The expression of Tlr4, Myd88, Nf-κb genes were evaluated by quantitative reverse transcription PCR (qRT-PCR) in different groups. The concentration of tumor necrosis factor alpha and Interleukin 1 beta in the cell culture medium were measured by enzyme-linked immunosorbent 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) production but not interleukin-1 β (IL-1β) in B16F10 LPS–stimulated cells in vitro. Moreover, treatment of B16F10 cells with TLR4 inhibitor prior treatment with pioglitazone indicate that the anticancer effects of pioglitazone on melanoma cells was dependent on TLR4.

Conclusion: The results indicate that pioglitazone has a beneficial protective effect against melanoma 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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