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治疗晚期肝细胞癌（HCC）的新型有效治疗方法。HCC是最常见的胃肠道（GI）恶性肿瘤之一，也是全球范围内死亡的主要原因，可用的治疗选择有限。因此，设计治疗这种疾病的安全有效的治疗方法至关重要。已知配体激活的核受体PPARγ调节多种癌细胞（包括HCC）的生长和分化。在我们早期的研究中，虽然其配体Troglitazone（TZD）激活PPARγ抑制HCC细胞增殖，但不能诱导任何凋亡。具有诱导生长停滞和细胞凋亡两者的潜力的药物（或组合）被认为在治疗晚期形式的癌症中最有效。为了确定TZD是否可以用作联合治疗，我们用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，TRAIL-TZD组合可以诱导一个显着程度的细胞凋亡的肝癌细胞相比，单独的药物治疗，并与显着增加裂解的聚（ADP-核糖）聚合酶（PARP）和半胱天冬酶3。更深入的研究旨在确定这种凋亡的分子靶点，以提高我们对肝癌细胞凋亡抵抗的效应子的理解。这些研究揭示，需要β-连环蛋白途径的完全拮抗来使HCC细胞对TRAIL-TZD诱导的凋亡敏感。由于TZD单独治疗通过新的机制在多个水平上拮抗β-catenin途径，并且β-catenin的拮抗作用促进HCC细胞凋亡，我们假设PPARγ（或TZD）通过拮抗β-catenin途径使HCC细胞对TRAIL敏感，否则HCC细胞对单独的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β-连环蛋白拮抗细胞凋亡和PPARγ拮抗β-连环蛋白的机制。我们提出了以下具体目标来实现我们的目标：（1）确定β-连环蛋白在介导HCC细胞存活和抗性中的作用，（2）确定β-连环蛋白在HCC细胞凋亡和存活过程中的调节机制，（3）确定β-连环蛋白在体内HCC存活和抗性中的作用.这些研究的成功完成预期将提供关于TRAIL-TZD组合对HCC细胞凋亡的功效的重要临床前数据，以及对β-连环蛋白是否充当介导凋亡抗性的分子靶标的基本理解。基于这些并且作为我们长期目标的一部分，可以设计更特异性的β-连环蛋白的下一代抑制剂（具有更少的附带毒性）以用于有效治疗患有晚期形式的HCC的患者的组合疗法。