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: 8694742
• 负责人: BASABI RANA
• 金额: $ 31.33万
• 依托单位: LOYOLA UNIVERSITY 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 2019-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8694742
• 关键词: Antineoplastic Agents; Apoptosis; Apoptotic; BAY 54-9085; Cause of Death; Cell Death; Cell Proliferation; Cell Survival; Cells; Characteristics; Combined Modality Therapy; Data; Development; Differentiation and Growth; Disease; Drug Combinations; Event; Future; Goals; Growth; In Vitro; Induction of Apoptosis; Ligands; Malignant Epithelial Cell; Malignant Neoplasms; Malignant neoplasm of liver; Mediating; Mediator of activation protein; Molecular; Molecular Target; Normal Cell; Nuclear Receptors; PI3K/AKT; Pathway interactions; Patients; Peroxisome Proliferator-Activated Receptors; 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-related apoptosis-inducing ligand; Testing; Therapeutic; Toxic effect; Tumor Necrosis Factor-alpha; Xenograft Model; base; beta catenin; cancer cell; caspase-3; cell growth; combat; combinatorial; design; effective therapy; gastrointestinal; hepatocellular carcinoma cell line; human FRAP1 protein; improved; in vivo; inhibitor/antagonist; liver cell proliferation; next generation; novel; overexpression; pre-clinical; public health relevance; 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 PPAR? is known to regulate growth and differentiation in a variety of cancer cells, including HCC. In our earlier studies although activation of PPAR? 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 ?-catenin pathway is needed to sensitize HCC cells towards TRAIL-TZD-induced apoptosis. Since treatment with TZD alone antagonized ?-catenin pathway at multiple levels via novel mechanisms, and antagonism of ?-catenin promoted HCC cell apoptosis, we hypothesize that PPAR? (or TZD) via antagonizing ?-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 ?-catenin antagonizes apoptosis and PPAR? antagonizes ?-catenin. The following specific aims are proposed to achieve our goals: (1) determine the role of ?-catenin in mediating HCC cell survival and resistance, (2) determine the mechanism by which ?-catenin is modulated during apoptosis and survival of HCC and (3) determine the role of ?-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 ?-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 ?-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型，有效的治疗方法，用于治疗晚期肝细胞癌（HCC）。 HCC是最常见的胃肠道（GI）恶性肿瘤之一，也是全球死亡的主要原因，可用的治疗选择有限。因此，设计安全有效的治疗方法来治疗这种疾病至关重要。配体激活的核受体PPAR？已知可以调节包括HCC在内的各种癌细胞的生长和分化。在我们较早的研究中，尽管激活了PPAR？通过其配体troglitazone（TZD）抑制了HCC细胞增殖，它无法诱导任何凋亡。据信具有诱导生长停滞和凋亡的潜力的药物（或组合）在治疗晚期癌症中最有效。为了确定是否可以将TZD用作联合疗法，我们将HCC细胞与促凋亡剂肿瘤坏死因子与凋亡相关的诱导配体（TRAIL）（TRAR）结合使用。我们的研究表明，与单独的药物治疗相比，TRAIL-TZD组合可以在HCC细胞中诱导大量的凋亡，并且与聚（ADP-核糖）聚合酶（PARP）和caspase 3的裂解显着增加有关。多次研究旨在确定对APT的影响，以改善APT的效果。这些研究表明，需要对hcc细胞敏感到TRAID-TZD诱导的细胞凋亡的完全拮抗作用。由于单独使用TZD治疗可以通过新的机制在多个级别上拮抗吗？ - 卡丁蛋白促进HCC细胞凋亡，我们假设该PPAR？ （或TZD）通过拮抗？ - 蛋白酶途径使HCC细胞朝向TRAIL敏感，否则它们对单独的步道不敏感。当前的提案旨在通过体外（细胞）和体内（异种移植）模型来验证我们的假设，同时阐明了？ - catenin拮抗细胞凋亡和PPAR的机制？对抗？ - 蛋白酶。提出了以下具体目的以实现我们的目标：（1）确定 - 蛋白酶在介导HCC细胞存活和抗性中的作用，（2）确定在HCC的凋亡和（3）在VIVO中使用HCC和抗性的作用的HCC和（3）在HCC和（3）中调节的机制。预计该研究的成功完成将提供有关TRAIL-TZD组合对HCC细胞凋亡的有效性的重要临床前数据，并且基本了解？-Catenin是否是介导凋亡耐药性的分子靶标。基于这些，作为我们长期目标的一部分，可以设计出更具体的下一代抑制剂（较少的附带毒性），可用于利用I组合疗法，以有效治疗具有晚期HCC的患者。