Peroxisome proliferator-activated receptor ligand MCC-555 suppresses intestinal polyps in ApcMin/+ mice via extracellular signal-regulated kinase and peroxisome proliferator-activated receptor-dependent pathways
Peroxisome proliferator-activated receptor ligand MCC-555 suppresses intestinal polyps in ApcMin/+ mice via extracellular signal-regulated kinase and peroxisome proliferator-activated receptor-dependent pathways
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DOI：
10.1158/1535-7163.mct-08-0173
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发表时间：
2008-09-01
影响因子：
5.7
通讯作者：
Baek, Seung Joon
中科院分区：
文献类型：
--
作者：
Yamaguchi, Kiyoshi;Cekanova, Maria;Baek, Seung Joon
大量研究表明，过氧化体增殖物激活受体γ(PPAR-γ)配体，如噻唑烷二酮，是有效的化学预防药物。MCC-555是一种PPARγ/α双重激动剂，已被证明在体外可以诱导细胞凋亡；然而，MCC-555在体内影响抗肿瘤形成的分子机制尚不清楚。在这项研究中，我们探讨了MCC-555在细胞培养和APC缺陷小鼠(一种人类家族性腺瘤性息肉病的动物模型)中的抗肿瘤作用。MCC-555增加MUC2在结直肠癌和肺癌细胞中的表达，用PPARγ拮抗剂GW9662处理后发现，MCC-555诱导MUC2的作用是通过PPARγ依赖的方式实现的。此外，MCC-555增加了人和小鼠MUC2启动子的转录活性。随后，MCC-555(30 mg/kg/d)治疗4周后，小鼠的小肠息肉数量减少到对照组的54.8%。与体外研究一致，MCC-555处理的小鼠小肠肿瘤中MUC2的表达增强，提示MUC2的表达可能至少部分与MCC-555的抗肿瘤作用有关。此外，在MCC-555处理的小鼠的肠道肿瘤中发现了高度磷酸化的细胞外信号调节激酶(ERK)，而一种特异性的抑制剂抑制ERK通路在体外显著抑制了MCC-555诱导的Muc2的表达。总体而言，这些结果表明，MCC-555在肠道肿瘤发生中具有强大的肿瘤抑制活性，可能涉及ERK和PPAR伽马通路上调MUC2。
A large body of studies has suggested that peroxisome proliferator-activated receptor gamma (PPAR-gamma) ligands, such as thiazolidinedione, are potent candidates for chemopreventive agents. MCC-555 is a PPAR gamma/alpha dual agonist and has been shown previously to induce apoptosis in vitro; however, the molecular mechanisms by which MCC-555 affects antitumorigenesis in vivo are poorly understood. In this study, we explored the antitumorigenic effects of MCC-555 both in cell culture and in Apc-deficient mice, an animal model for human familial adenomatous polyposis. MCC-555 increased MUC2 expression in colorectal and lung cancer cells, and treatment with the PPAR gamma antagonist GW9662 revealed that MUC2 induction by MCC-555 was mediated in a PPAR gamma-dependent manner. Moreover, MCC-555 increased transcriptional activity of human and mouse MUC2 promoters. Subsequently, treatment with MCC-555 (30 mg/kg/d) for 4 weeks reduced the number of small intestinal polyps to 54.8% of that in control mice. In agreement with in vitro studies, enhanced Muc2 expression was observed in the small intestinal tumors of Min mice treated with MCC-555, suggesting that MUC2 expression may be associated at least in part with the antitumorigenic action of MCC-555. In addition, highly phosphorylated extracellular signal-regulated kinase (ERK) was found in the intestinal tumors of MCC-555-treated Min mice, and inhibition of the ERK pathway by a specific inhibitor markedly suppressed MCC-555-induced Muc2 expression in vitro. Overall, these results indicate that MCC-555 has a potent tumor suppressor activity in intestinal tumorigenesis, likely involving MUC2 up-regulation by ERK and PPAR gamma pathways.