Isorhamnetin Inhibits Proliferation and Invasion and Induces Apoptosis through the Modulation of Peroxisome Proliferator-activated Receptor γ Activation Pathway in Gastric Cancer
Isorhamnetin Inhibits Proliferation and Invasion and Induces Apoptosis through the Modulation of Peroxisome Proliferator-activated Receptor γ Activation Pathway in Gastric Cancer
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DOI：
10.1074/jbc.m112.388702
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发表时间：
2012-11-02
影响因子：
4.8
通讯作者：
Sethi, Gautam
中科院分区：
文献类型：
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作者：
Ramachandran, Lalitha;Manu, Kanjoormana Aryan;Sethi, Gautam
胃癌(GC)是一种致命的恶性肿瘤，是癌症相关死亡的第二大常见原因。虽然化疗、放疗和手术等治疗方法降低了GC的死亡率，但化疗耐药仍然是预后差和复发率高的主要原因之一。在这项研究中，我们利用蛋白质组学技术平台、GC细胞系和异种移植小鼠模型，研究了异鼠李素(IH)对PPAR-γ信号转导通路的影响。我们观察到IH与化疗药物联合应用具有较强的抗增殖作用和细胞毒作用。IH还抑制GC细胞的迁移/侵袭特性，这种抑制作用可以在PPAR-γ抑制剂的存在下逆转。我们发现，IH增加了GC细胞中PPAR-γ的活性，并调节了PPAR-γ调节基因的表达。此外，在PPAR-γ特异性抑制剂和突变的PPAR-γ显性负质粒的存在下，PPAR-γ活性的增加被逆转，这支持了我们的假设，即IH可以作为PPAR-γ的配体。通过分子对接分析，我们证明了IH与PPAR-Gamma配体结合口袋中的7个极性残基和6个非极性残基形成了相互作用，这是其活性的关键，并可以竞争性地与PPAR-Gamma结合。IH能显著增加胃癌移植瘤组织中PPAR-γ的表达。总体而言，我们的研究结果清楚地表明，IH的抗肿瘤作用可能是通过调节GC中PPAR-Gamma激活途径来实现的。
Gastric cancer (GC) is a lethal malignancy and the second most common cause of cancer-related deaths. Although treatment options such as chemotherapy, radiotherapy, and surgery have led to a decline in the mortality rate due to GC, chemoresistance remains as one of the major causes for poor prognosis and high recurrence rate. In this study, we investigated the potential effects of isorhamnetin (IH), a 3'-O-methylated metabolite of quercetin on the peroxisome proliferator-activated receptor gamma (PPAR-gamma) signaling cascade using proteomics technology platform, GC cell lines, and xenograft mice model. We observed that IH exerted a strong antiproliferative effect and increased cytotoxicity in combination with chemotherapeutic drugs. IH also inhibited the migratory/invasive properties of GC cells, which could be reversed in the presence of PPAR-gamma inhibitor. We found that IH increased PPAR-gamma activity and modulated the expression of PPAR-gamma regulated genes in GC cells. Also, the increase in PPAR-gamma activity was reversed in the presence of PPAR-gamma-specific inhibitor and a mutated PPAR-gamma dominant negative plasmid, supporting our hypothesis that IH can act as a ligand of PPAR-gamma. Using molecular docking analysis, we demonstrate that IH formed interactions with seven polar residues and six nonpolar residues within the ligand-binding pocket of PPAR-gamma that are reported to be critical for its activity and could competitively bind to PPAR-gamma. IH significantly increased the expression of PPAR-gamma in tumor tissues obtained from xenograft model of GC. Overall, our findings clearly indicate that antitumor effects of IH may be mediated through modulation of the PPAR-gamma activation pathway in GC.