PPAR γ Agonist, Pioglitazone, Suppresses Melanoma Cancer in Mice by Inhibiting TLR4 Signaling
PPAR γ Agonist, Pioglitazone, Suppresses Melanoma Cancer in Mice by Inhibiting TLR4 Signaling
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DOI：
10.18433/jpps30626
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发表时间：
2019-09-08
影响因子：
2.7
通讯作者：
Javanmard, Shaghayegh Haghjooy
中科院分区：
文献类型：
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作者：
Dana, Nasim;Vaseghi, Golnaz;Javanmard, Shaghayegh Haghjooy
背景：虽然已有研究表明过氧化物酶体增殖物激活受体γ (PPAR γ)的配体通过激活其抗炎反应而具有抗癌作用，但PPAR γ的抗肿瘤机制尚未得到深入研究。参与癌症进展的分子之一是toll样受体4 （TLR4）。TLR4信号传导诱导nf - κ B活性，在癌症进展中起关键作用。在这项研究中，我们检测了黑色素瘤中PPAR γ和TLR4之间的串扰。方法：B16F10黑色素瘤细胞在LPS和不LPS的作用下培养24小时。将细胞皮下注射到两组C57BL/6小鼠。可触及肿瘤形成后，将各组动物分为4个亚组，分别按不同剂量（0、10、50、100 mg/kg/d）给予吡格列酮治疗10天。研究结束时，采用qRT-PCR方法检测不同组小鼠肿瘤中Tlr4、Myd-88、Nf-kb1基因的表达。免疫组化法检测tlr - α蛋白表达。采用ELISA试剂盒检测小鼠肿瘤及血清中tnf - α水平。用游标卡尺测量肿瘤体积。结果：我们观察到PPAR γ被其激动剂吡格列酮激活后，黑色素瘤肿瘤体积、Tlr-4、Myd-88、Nf-kb1 mRNA表达、TLR4蛋白表达和tnf - α产生减少，特别是在注射LPS刺激细胞的组中。此外，用吡格列酮治疗黑色素瘤细胞表明，吡格列酮对lps诱导的炎症反应的抑制作用依赖于TLR4。结论：PPAR γ激动剂吡格列酮通过干扰tlr4依赖性信号通路对黑色素瘤具有有益的保护作用。
Background: Although previous studies demonstrated an anticancer effect for the ligands of peroxisome proliferator-activated receptor gamma (PPAR gamma) through activation of its anti-inflammatory responses, nevertheless the anti-tumor mechanism of PPAR gamma has not been intensively investigated. One of the molecules involved in cancer progression is toll-like receptor 4 (TLR4). TLR4 signaling induces NF-kappa B activity which has a crucial role in cancer progression. In this study, we examined the cross-talk between PPAR gamma and TLR4 in the melanoma. Methods: B16F10 melanoma cells were cultured with or without LPS for 24 hr. The cells were subcutaneously injected to two groups of C57BL/6 mice. After the development of palpable tumors each group of animals were divide to four sub-groups and received pioglitazone in different dose ranges (0,10,50,100 mg/kg/day) for 10 days. At the end of the study, the expression of Tlr4, Myd-88, Nf-kb1 genes was evaluated by qRT-PCR in different groups in mice tumor. The TLR-alpha protein expression was evaluated by IHC. TNF-alpha level in mice tumor and serum were measured by ELISA kits. Tumor volume was measured with Vernier calipers. Results: We observed that activation of PPAR gamma by its agonist, pioglitazone, reduces tumor volume, Tlr-4, Myd-88, Nf-kb1 mRNA expression, TLR4 protein expression and TNF-alpha production 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 LPS-induced inflammatory responses were TLR4 dependent. Conclusion: The results indicate that pioglitazone, a PPAR gamma agonist, has a beneficial protective effect against melanoma via interfering with the TLR4-dependent signaling pathways.