Cross-regulation of apoptosis and autophagy as a molecular basis for reversal of

细胞凋亡和自噬的交叉调节作为逆转细胞凋亡的分子基础

• 批准号: 8270354
• 负责人: HANNAH RABINOWICH
• 金额: $ 30.22万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-05-05 至 2014-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8270354
• 关键词: Antibodies; Antineoplastic Agents; Apoptosis; Apoptotic; Autophagocytosis; Autophagosome; Binding; Biological; Caspase; Cell Culture Techniques; Cell Death; Cell Proliferation; Cell Survival; Cells; Cellular Stress; Cessation of life; Cleaved cell; Clinical Protocols; Cytotoxic Chemotherapy; Defect; Development; Diagnostic Neoplasm Staging; Disabled Persons; Disease; Event; Goals; Growth Factor; Health; Lysosomes; Malignant - descriptor; Mediating; Membrane; Molecular; Multi-Drug Resistance; Mutation; Necrosis; Normal Cell; Nutrient; Organelles; Population; Predisposition; Process; Proteins; Recombinants; Regimen; Regulation; Repression; Research Design; Resistance; Role; Signal Pathway; Signal Transduction; Starvation; Stress; System; TNFRSF10A gene; TNFRSF10B gene; TNFSF10 gene; Testing; Therapeutic; Therapeutic Agents; Tumor Cell Line; Tumor stage; Vesicle; abstracting; base; cancer cell; cancer therapy; caspase-8; cell growth; cytotoxic; deprivation; inhibition of autophagy; interest; irradiation; neoplastic cell; novel; resistance mechanism; response; stem; therapy resistant; tumor; tumor growth; tumor progression; tumorigenesis

DESCRIPTION (provided by applicant): Abstract Defects in apoptotic capability that evolve during tumorigenesis promote tumor growth, provide survival advantage, and confound treatment. Such defects have been a major hurdle in the development of TRAIL therapy. Targeting TRAIL-Rs with either recombinant TRAIL or agonistic DR4 or DR5-specific antibodies has been considered a promising treatment for cancer, particularly due to the preferential apoptotic susceptibility of tumor cells to TRAIL over normal cells. However, the realization that many tumors are unresponsive to TRAIL treatment has stimulated interest in identifying apoptotic agents that when used in combination with TRAIL can sensitize tumor cells to TRAIL-mediated apoptosis. Our preliminary studies suggest that various apoptosis defects that block TRAIL-mediated cell death at different points along the apoptotic signaling pathway shift the signaling cascade from default apoptosis toward cytoprotective autophagy. We also obtained substantial evidence that inhibition of such a TRAIL-mediated autophagic response initiates an effective apoptotic cascade. We propose to investigate a novel concept that divergent mechanisms of resistance to TRAIL- mediated apoptosis involve the induction of protective autophagy, and thus can be reversed by targeting for inhibition specific components of the autophagic process. We hypothesize that inhibition of autophagy can be utilized for TRAIL therapy since it reverses certain mechanisms of TRAIL resistance in apoptosis- defective tumor cells. We further hypothesize that essential components of the autophagosome formation process, particularly Beclin-1/Atg6, UVRAG, Vps34 and Atg7, are involved in a constant crosstalk between autophagy and apoptosis through their dual function of mediating autophagy and inhibiting apoptosis. Thus, the knockdown of such proteins would not only block autophagy, but would also initiate apoptotic events in a manner that depends on the antiapoptotic function of the targeted Atg protein. Although the proposed studies focus on mechanisms of resistance to TRAIL therapy, they are highly relevant to a broader goal of eradicating multidrug-resistant cancer cells, as they target a major stumbling block in numerous cytotoxic regimens, i.e., defects in apoptotic capability that evolve during tumorigenesis. The proposed studies are designed to elucidate molecular mechanisms involved in the mutual inhibition between autophagy and apoptosis. A better understanding of the molecular basis for the cross regulation between autophagy and apoptosis will help determine if modulation of autophagy can be utilized for cancer therapy. PUBLIC HEALTH RELEVANCE: Our preliminary results suggest that numerous cellular mechanisms within tumor cells that commonly interfere with the efficacy of the anticancer drug, TRAIL, involve the activation of a cytoprotective response. We also obtained evidence that inhibition of such a cellular protective response yields a productive cell death. The goal of the current application is to elucidate the molecular mechanisms that underlie the reversal of tumor cell resistance to TRAIL therapy.

描述（由申请人提供）：摘要肿瘤发生过程中出现的细胞凋亡能力缺陷促进肿瘤生长，提供生存优势，并混淆治疗。这些缺陷一直是 TRAIL 疗法发展的主要障碍。用重组 TRAIL 或激动性 DR4 或 DR5 特异性抗体靶向 TRAIL-R 已被认为是一种有前途的癌症治疗方法，特别是由于肿瘤细胞比正常细胞对 TRAIL 具有优先的凋亡敏感性。然而，认识到许多肿瘤对 TRAIL 治疗没有反应，激发了人们对鉴定凋亡药物的兴趣，这些药物与 TRAIL 联合使用时可以使肿瘤细胞对 TRAIL 介导的细胞凋亡敏感。我们的初步研究表明，多种细胞凋亡缺陷在细胞凋亡信号通路的不同点阻断 TRAIL 介导的细胞死亡，从而将信号级联从默认细胞凋亡转变为细胞保护性自噬。我们还获得了大量证据表明，抑制这种 TRAIL 介导的自噬反应会引发有效的细胞凋亡级联反应。我们建议研究一个新的概念，即抵抗 TRAIL 介导的细胞凋亡的不同机制涉及诱导保护性自噬，因此可以通过靶向抑制自噬过程的特定成分来逆转。我们假设自噬的抑制可用于 TRAIL 治疗，因为它逆转了凋亡缺陷肿瘤细胞中 TRAIL 抵抗的某些机制。我们进一步假设自噬体形成过程的重要组成部分，特别是 Beclin-1/Atg6、UVRAG、Vps34 和 Atg7，通过介导自噬和抑制细胞凋亡的双重功能参与自噬和细胞凋亡之间的持续串扰。因此，此类蛋白质的敲低不仅会阻止自噬，而且还会以取决于目标 Atg 蛋白质的抗凋亡功能的方式启动凋亡事件。尽管拟议的研究重点关注 TRAIL 疗法的耐药机制，但它们与根除多重耐药癌细胞的更广泛目标高度相关，因为它们针对的是许多细胞毒性疗法中的主要障碍，即肿瘤发生过程中演变的细胞凋亡能力的缺陷。拟议的研究旨在阐明自噬和凋亡之间相互抑制的分子机制。更好地了解自噬和细胞凋亡之间交叉调节的分子基础将有助于确定自噬的调节是否可用于癌症治疗。公共健康相关性：我们的初步结果表明，肿瘤细胞内的许多细胞机制通常会干扰抗癌药物 TRAIL 的功效，这些机制涉及细胞保护反应的激活。我们还获得证据表明，抑制这种细胞保护反应会导致有效的细胞死亡。当前应用的目标是阐明逆转肿瘤细胞对 TRAIL 疗法耐药性的分子机制。