Role of beta-catenin in apoptosis resistance of hepatocellular carcinoma

β-catenin在肝细胞癌凋亡抵抗中的作用

• 批准号: 9487175
• 负责人: BASABI RANA
• 金额: $ 33.18万
• 依托单位: UNIVERSITY OF ILLINOIS AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-06-01 至 2020-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9487175
• 关键词: Antineoplastic Agents; Apoptosis; Apoptotic; BAY 54-9085; CASP3 gene; Cause of Death; Cell Death; Cell Proliferation; Cell Survival; Cells; Characteristics; Combined Modality Therapy; Data; Development; Diagnostic; Differentiation and Growth; Disease; Drug Combinations; Drug Targeting; Event; FRAP1 gene; Future; Goals; Growth; In Vitro; Induction of Apoptosis; Ligands; Malignant Epithelial Cell; Malignant Neoplasms; Malignant neoplasm of gastrointestinal tract; Malignant neoplasm of liver; Mediating; Mediator of activation protein; Molecular; Molecular Target; Necrosis; Normal Cell; Nuclear Receptors; PI3K/AKT; PPAR gamma; Pathway interactions; Patients; Pharmaceutical Preparations; Pharmacotherapy; Poly(ADP-ribose) Polymerases; Primary carcinoma of the liver cells; Proliferating; Property; Proteins; Publishing; Ras/Raf; Reporting; Research; Resistance; Role; Signal Transduction; TNF gene; TNF-related apoptosis-inducing ligand; TP53 gene; Testing; Therapeutic; Toxic effect; Treatment Efficacy; WNT Signaling Pathway; Xenograft Model; base; beta catenin; cancer cell; cell growth; combat; combinatorial; design; effective therapy; hepatocellular carcinoma cell line; improved; in vivo; inhibitor/antagonist; knock-down; liver cell proliferation; next generation; novel; overexpression; pre-clinical; public health relevance; rapid growth; therapeutic development; troglitazone

DESCRIPTION (provided by applicant): The overall long-term goal of the proposed research is to design a novel and efficient therapeutic approach for treating advanced hepatocellular carcinoma (HCC). HCC is one of the most common gastrointestinal (GI) malignancies and a major cause of death worldwide, with limited available therapeutic options. Designing safe and efficient therapeutic approaches for treating this disease is thus critically important. Ligand-activated nuclear receptor PPARγ is known to regulate growth and differentiation in a variety of cancer cells, including HCC. In our earlier studies although activation of PPARγ by its ligand Troglitazone (TZD) inhibited HCC cell proliferation, it was unable to induce any apoptosis. The drugs (or combinations) which have the potential of inducing both growth arrest and apoptosis are believed to be most effective in treating advanced forms of cancer. To determine whether TZD can be utilized as a combination therapy instead, we treated HCC cells with TZD in combination with the proapoptotic agent Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL). Our studies indicated that TRAIL-TZD combination can induce a significant degree of apoptosis in the HCC cells compared to either drug treatment alone and was associated with a dramatic increase in the cleavage of poly (ADP-ribose) polymerase (PARP) and Caspase 3. More in-depth studies were designed to identify the molecular target of this apoptosis, in an effort to improve our understanding of the effectors involved in apoptosis resistance of HCC. These studies revealed that a complete antagonism of ß-catenin pathway is needed to sensitize HCC cells towards TRAIL-TZD-induced apoptosis. Since treatment with TZD alone antagonized ß-catenin pathway at multiple levels via novel mechanisms, and antagonism of ß-catenin promoted HCC cell apoptosis, we hypothesize that PPARγ (or TZD) via antagonizing ß-catenin pathway sensitizes HCC cells towards TRAIL, which are otherwise insensitive to TRAIL alone. The current proposal aims to validate our hypothesis utilizing both in vitro (cellular) and in vivo (xenograft) models while elucidating the mechanisms by which ß-catenin antagonizes apoptosis and PPARγ antagonizes ß-catenin. The following specific aims are proposed to achieve our goals: (1) determine the role of ß-catenin in mediating HCC cell survival and resistance, (2) determine the mechanism by which ß-catenin is modulated during apoptosis and survival of HCC and (3) determine the role of ß-catenin on HCC survival and resistance in vivo. Successful completion of the studies is expected to provide important preclinical data on the efficacy of TRAIL-TZD combination on HCC cell apoptosis and a fundamental understanding whether ß-catenin serves as a molecular target to mediate apoptotic resistance. Based on these and as part of our long-term goal, more specific next generation inhibitors of ß-catenin (with less collateral toxicity) can be designed to be utilized i combination therapies for effectively treating patients with advanced forms of HCC.

描述（由申请人提供）：拟议研究的总体长期目标是设计一种新颖有效的治疗晚期肝细胞癌（HCC）的治疗方法。HCC是最常见的胃肠道（GI）恶性肿瘤之一，也是世界范围内死亡的主要原因，可用的治疗方案有限。因此，设计安全有效的治疗方法来治疗这种疾病至关重要。已知配体激活的核受体PPARγ调节多种癌细胞的生长和分化，包括HCC。在我们早期的研究中，虽然PPARγ的配体Troglitazone （TZD）激活可以抑制HCC细胞的增殖，但它不能诱导任何细胞凋亡。具有诱导生长停滞和细胞凋亡的潜力的药物（或组合）被认为是治疗晚期癌症最有效的药物。为了确定TZD是否可以作为一种联合治疗方法，我们将TZD与促凋亡剂肿瘤坏死因子相关凋亡诱导配体（TRAIL）联合治疗HCC细胞。我们的研究表明，与单独用药相比，TRAIL-TZD联合用药可显著诱导HCC细胞凋亡，并与聚（adp -核糖）聚合酶（PARP）和Caspase 3切割的显著增加有关。我们设计了更深入的研究来确定这种凋亡的分子靶点，以提高我们对参与HCC细胞凋亡抵抗的效应物的理解。这些研究表明，需要完全拮抗ß-catenin通路才能使HCC细胞对trail - tzd诱导的凋亡敏感。由于单独使用TZD通过新的机制在多个水平上拮抗ß-catenin通路，并且ß-catenin的拮抗作用促进了HCC细胞的凋亡，我们假设PPARγ（或TZD）通过拮抗ß-catenin通路使HCC细胞对TRAIL增敏，否则它们对TRAIL不敏感。目前的建议旨在利用体外（细胞）和体内（异种移植）模型验证我们的假设，同时阐明ß-catenin拮抗细胞凋亡和PPARγ拮抗ß-catenin的机制。为了实现我们的目标，我们提出了以下具体目标：(1)确定ß-catenin在介导HCC细胞存活和耐药中的作用；(2)确定ß-catenin在HCC细胞凋亡和存活过程中的调节机制；(3)确定ß-catenin在体内对HCC存活和耐药的作用。这些研究的成功完成有望为TRAIL-TZD联合治疗HCC细胞凋亡的疗效提供重要的临床前数据，并从基础上了解ß-catenin是否作为介导凋亡耐药的分子靶点。在此基础上，作为我们长期目标的一部分，可以设计出更特异性的下一代ß-catenin抑制剂（附带毒性更小），用于联合治疗，有效治疗晚期HCC患者。