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: 8854052
• 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 2015-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8854052
• 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; Drug Targeting; Event; Future; Goals; Growth; Health; 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; 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-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; hepatocellular carcinoma cell line; human FRAP1 protein; improved; in vivo; inhibitor/antagonist; liver cell proliferation; next generation; novel; overexpression; pre-clinical; 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且有效的治疗方法来治疗晚期肝细胞癌（HCC）。 HCC 是最常见的胃肠道 (GI) 恶性肿瘤之一，也是全世界死亡的主要原因，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。众所周知，配体激活的核受体 PPARγ 可调节多种癌细胞（包括 HCC）的生长和分化。在我们早期的研究中，尽管其配体曲格列酮（TZD）激活PPARγ可抑制HCC细胞增殖，但无法诱导任何细胞凋亡。具有诱导生长停滞和细胞凋亡潜力的药物（或组合）被认为在治疗晚期癌症方面最有效。为了确定 TZD 是否可以用作联合疗法，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，与单独使用任一药物治疗相比，TRAIL-TZD 组合可诱导 HCC 细胞显着程度的细胞凋亡，并且与聚（ADP-核糖）聚合酶（PARP）和 Caspase 3 裂解的显着增加有关。更深入的研究旨在确定这种细胞凋亡的分子靶点，以提高我们对参与 HCC 细胞凋亡抵抗的效应器的了解。这些研究表明，需要完全拮抗 ß-连环蛋白途径来使 HCC 细胞对 TRAIL-TZD 诱导的细胞凋亡敏感。由于单独使用 TZD 治疗可通过新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 HCC 细胞凋亡，因此我们假设 PPARγ（或 TZD）通过拮抗 ß-catenin 通路使 HCC 细胞对 TRAIL 敏感，而 HCC 细胞对单独的 TRAIL 不敏感。目前的提案旨在利用体外（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，提出了以下具体目标：（1）确定β-连环蛋白在介导HCC细胞存活和耐药中的作用，（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，以及（3）确定β-连环蛋白在体内HCC存活和耐药中的作用。研究的成功完成预计将为 TRAIL-TZD 组合对 HCC 细胞凋亡的功效提供重要的临床前数据，并从根本上了解 ß-catenin 是否作为介导细胞凋亡抵抗的分子靶点。基于这些，并作为我们长期目标的一部分，可以设计更特异的下一代β-连环蛋白抑制剂（附带毒性较小），用于联合疗法，有效治疗晚期 HCC 患者。