مقالات پذیرفته شده در سومین کنگره بین المللی زیست پزشکی
Pioglitazone inhibits melanoma tumor growth in vivo via interfering with the TLR4 signaling pathways
Pioglitazone inhibits melanoma tumor growth in vivo via interfering with the TLR4 signaling pathways
Nasim Dana,1,*Golnaz Vaseghi,2Shaghayegh Haghjooy Javanmard,3
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 3. Applied Physiology Research Center, Cardiovascular Research Institute, Isfahan University of Medical sciences, Isfahan, Iran
Introduction: Background: Although previous studies demonstrated an anticancer effect for the ligands of peroxisome proliferator-activated receptor gamma (PPARγ) through activation of their anti-inflammatory responses, nevertheless the anti-tumor mechanism of PPARγ has not been intensively investigated. It has been demonstrated that PPAR-γ ligands regulate inflammatory response genes by inhibiting NF-κB. One of the molecules involved in cancer progression is toll-like receptor 4 (TLR4). TLR4 can exert its effects through an independent Myd-88 pathway, with a reported delay in NF-κB activation. Previously we have shown that Stimulation of TLR4 on melanoma cells with a specific ligand (lipopolysaccharides: LPS) up regulates Tlr4, Myd-88 and Nf-κB mRNA expression and increased their proliferation. The present study aimed to investigate whether pioglitazone, a ligand of PPAR-γ, inhibits melanoma tumor growth cancer via interfering with the TLR4 signaling pathways.
Methods: Methods: Before tumor cell injection, B16F10 melanoma cells were cultured with or without LPS for 24 hours. Following the subcutaneous injection of these cells to the two main groups of C57BL/6 mice and tumor development (after 7 days), each group was divided into four sub-groups. The sub-groups received pioglitazone in different dose ranges (0,10,50,100 mg/kg/day) for 10 days. At the end of the study, tumor volume was measured with Vernier calipers in different groups. The Tlr4, Myd-88 and Nf-κb mRNA and TLR4 protein expression was evaluated by QRT-PCR and IHC respectively.
Results: Results: Our results have shown that activation of PPARγ by its agonist, pioglitazone, significantly reduces tumor volume, Tlr4 Myd-88 and Nf-κb mRNA and TLR4 protein expression in melanoma tumor especially in groups that were injected with LPS –stimulated cells. Moreover, treatment of melanoma cells with pioglitazone showed that the inhibitory effects of pioglitazone on melanoma cells were TLR4 dependent.
Conclusion: Conclusions: These results suggest that pioglitazone has a beneficial protective effect against melanoma via interfering with the TLR4-dependent signaling pathways.