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。配体激活的核受体已知其调节多种癌细胞（包括HCC）的生长和分化。在我们早期的研究，虽然激活的过氧化物酶体增殖物激活受体？通过其配体Troglitazone（TZD）抑制HCC细胞增殖，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。这些研究表明，完全拮抗？-需要连环蛋白途径来使HCC细胞对TRAIL-TZD诱导的凋亡敏感。因为TZD单独治疗拮抗？-通过新的机制在多个水平上的连环蛋白通路，以及？catenin促进肝癌细胞凋亡，我们推测，过氧化物酶体增殖物激活受体？(or TZD）通过对抗？-连环蛋白途径使HCC细胞对TRAIL敏感，否则其对单独的TRAIL不敏感。目前的建议旨在利用体外（细胞）和体内（异种移植）模型来验证我们的假设，同时阐明？catenin拮抗细胞凋亡和PPAR？对抗？连环蛋白。为了实现我们的目标，提出了以下具体目标：（1）确定？连环蛋白在介导HCC细胞存活和抵抗中的作用，（2）确定其机制？连环蛋白在肝癌细胞凋亡和存活过程中受到调节，（3）决定？连环蛋白对HCC存活和抵抗的影响。这些研究的成功完成预计将提供关于TRAIL-TZD组合对HCC细胞凋亡的功效的重要临床前数据，并从根本上了解TRAIL-TZD组合是否对HCC细胞凋亡有影响。连环蛋白作为介导细胞凋亡抗性的分子靶标。基于这些，并作为我们长期目标的一部分，更具体的下一代抑制剂？-连环蛋白（具有较少的附带毒性）可被设计用于联合疗法，以有效治疗患有晚期形式的HCC的患者。