PPARγ激动剂增敏ABT-263抗肝细胞癌的作用及分子机制研究

项目名称： PPARγ激动剂增敏ABT-263抗肝细胞癌的作用及分子机制研究

项目编号： No.81472291

项目类型： 面上项目

立项/批准年度： 2015

项目学科： 医药、卫生

项目作者： 何凤田

作者单位： 中国人民解放军第三军医大学

项目金额： 90万元

中文摘要： Bcl-xL/Bcl-2抑制剂ABT-263在抗包括肝细胞癌（HCC）在内的多种肿瘤方面已显示出良好的应用前景，但其上调Mcl-1的作用严重削弱了其抗癌效应。我们前期创新性发现：核受体PPARγ的激动剂可增敏ABT-263杀伤HCC细胞的能力、可抑制ABT-263对Mcl-1的上调以及JNK和mTOR的磷酸化，同时能促进DUSP16的表达以及AMPK的磷酸化。据此提出假设：PPARγ激动剂可能通过调节DUSP16→JNK和AMPK→mTOR这两条信号通路而抑制ABT-263对Mcl-1的上调，从而增敏ABT-263的抗HCC效应。本项目将解析PPARγ激动剂调控上述两条通路的分子机制，揭示DUSP16是PPARγ的一个新靶基因；进而在HCC细胞模型及荷瘤鼠模型上探讨这两条通路在PPARγ激动剂增敏ABT-263抗HCC效应中的重要性，为探索基于上述增敏机制的抗HCC新措施提供科学依据。

中文关键词： C09_肝和肝内胆管肿瘤；过氧化物酶体增殖物激活受体γ；肝细胞癌；ABT-263；增敏

英文摘要： ABT-263, an inhibitor of Bcl-xL(B cell lymphoma-extra large)/Bcl-2(B cell lymphoma 2), has shown promising antitumor efficacy in multiple cancers including hepatocellular carcinoma(HCC). However, its antitumor efficacy is markedly weakened by upregulating Mcl-1(myeloid cell leukemia 1). Our preliminary novel data showed that the agonists for nuclear receptor PPARγ(peroxisome proliferator activated receptor gamma) sensitized ABT-263-induced growth inhibition in HCC cells, dramatically attenuated ABT-263-mediated upregulation of Mcl-1 and phosphorylation of JNK(c-Jun N-terminal kinase) and mTOR(mammalian target of rapamycin), and promoted the expression of DUSP16(dual specificity phosphatase 16) and phosphorylation of AMPK(adenosine monophosphate activated protein kinase). Based on the above novel discoveries, we hypothesize that PPARγ agonists may repress ABT-263-induced Mcl-1 by regulating DUSP16→JNK and AMPK→mTOR pathways, which sensitizes ABT-263-mediated anti-HCC efficacy. In this project, we will illustrate the mechanisms by which PPARγ agonists regulate the above two mentioned signaling pathways, and verify that DUSP16 is a novel target gene of PPARγ. Furthermore, the HCC cells and tumor-bearing mice will be engagaed to evaluate the importance of the two signaling pathways in PPARγ agonists-mediated sensitization to ABT-263-induced anti-HCC efficacy, which aims to provide scientific evidences for exploring novel anti-HCC strategy based on the above sensitizing mechanisms.

英文关键词： Hepatobiliary malignancies;Peroxisome proliferator activated receptor gamma;Hepatocellular carcinoma;ABT-263;Sensitization