UNFOLDED PROTEIN RESPONSE IN DRUG SENSITIVITY AND RESISTANCE

药物敏感性和耐药性中未折叠的蛋白质反应

• 批准号: 7313997
• 负责人: Linda M Hendershot
• 金额: $ 27.01万
• 依托单位: ST. JUDE CHILDREN'S RESEARCH HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-07-01 至 2012-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7313997
• 关键词: Affect; Aftercare; Angiogenesis Inhibitors; Angiogenic Factor; Animal Model; Animals; Antineoplastic Agents; Apoptotic; Buffers; Carmustine; Cell Cycle Arrest; Cell physiology; Cells; Characteristics; Cisplatin; Class; Collaborations; Coupled; Cultured Cells; DNA Damage; Data; Doctor of Philosophy; Drug resistance; Elements; Embryo; Engineering; Fibroblasts; Funding; Gene Targeting; Genetic Transcription; Human; Knock-out; Malignant Childhood Neoplasm; Mediating; Molecular Chaperones; Mus; Numbers; Pathway interactions; Pediatric Neoplasm; Personal Satisfaction; Pharmaceutical Preparations; Play; Poison; Process; Proteins; Range; Regulatory Element; Research Personnel; Resistance; Role; Sampling; Stress; Testing; Tissue Array Analysis; Topoisomerase II; Topotecan; Toxic effect; Transcription Process; Transcriptional Activation; Type I DNA Topoisomerases; Up-Regulation; Upper arm; Vascular Endothelial Growth Factors; Vascular blood supply; Vascular remodeling; Vascularization; Xenograft Model; Xenograft procedure; antitumor agent; cell killing; chemotherapeutic agent; clinically relevant; drug efficacy; drug sensitivity; experience; genetic analysis; human TOP1 protein; molecular pathology; neoplastic cell; programs; promoter; protein folding; research study; response; temozolomide; tumor; tumor growth

Due to inadequate blood supply, tumor cells exist in a compromised microenvironment that impinges on normal protein folding and can activate the unfolded protein response (DPR). In addition to contributing to tumor growth and survival, data from cell culture studies demonstrate that pharmacological activation of the UPR can also alter the sensitivity of cells to chemotherapeutic agents, making them more sensitive in some cases and more resistant in others. In the previous cycle of funding, we showed that UPR activation is both necessary and sufficient to reduce the sensitivity to topoisomerase II targeted therapy and found that this is a result of PERK activation. We propose genetic analyses in the coming cycle to identify the responsible target(s) and determine to what extent the UPR affects drug sensitivity in xenograft studies. Conversely, UPR activation increases the sensitivity of cells to cisplatin, which damages both DMA and proteins. As a number of anti-cancer agents have similar characteristics, we propose to explore interactions between these agents and the UPR and to determine the mechanism or interaction where synergies exist. Given the broad affects of the UPR on cellular processes, it is likely that this pathway will interact with other chemotherapeutic agents. Indeed, our preliminary data demonstrate that activation of the UPR reduces the sensitivity of cells to the topoisomerase I poison, topotecan. Finally, anti-angiogenic agents are being used to inhibit tumor vascularization, which should contribute to UPR activation in the tumor. However, recent data demonstrate that they can also promoter vascular remodeling, making it unclear how this will affect UPR activation. Since the UPR leads to both increased transcription and processing of pro-angiogenic factors, it is essential to understand the affect of anti-angiogenic agents on the UPR and to determine if the UPR plays a role in resistance to these agents. In this proposal, we describe experiments to determine the mechanisms by which the UPR increases sensitivity to some agents while decreasing sensitivity to others, explore possible interactions with additional chemotherapeutic agents, and determine the affect of UPR activation on drug sensitivity in animal models. In addition, we will extend our initial examination of UPR activation in tumor samples to other UPR targets and multiple types of tumors to establish the scope of the significance of our findings to pediatric cancers.

由于血液供应不足，肿瘤细胞存在于受损的微环境中 正常蛋白质折叠，可以激活未折叠的蛋白质反应（DPR）。除了贡献 肿瘤的生长和生存，来自细胞培养研究的数据表明，药理学激活 UPR还可以改变细胞对化学治疗剂的敏感性，使其在某些人中更敏感 案例和其他案例更具抵抗力。在上一个资金周期中，我们表明UPR激活既是 必要和足够的足以降低对拓扑异构酶II的敏感性靶向治疗，发现这是一个 PERK激活的结果。我们提出在即将到来的周期中进行遗传分析，以确定负责任的 目标并确定UPR在异种移植研究中影响药物敏感性的程度。反过来， UPR激活增加了细胞对顺铂的敏感性，从而损害了DMA和蛋白质。作为 抗癌药的数量具有相似的特征，我们建议探索这些特征 代理和UPR，并确定存在协同作用的机制或相互作用。鉴于广泛 UPR对蜂窝过程的影响，该途径可能会与其他相互作用 化学治疗剂。确实，我们的初步数据表明，UPR的激活减少了 细胞对拓扑异构酶I毒药的敏感性。最后，正在使用抗血管生成剂 为了抑制肿瘤血管形成，这应导致肿瘤中的UPR激活。但是，最近 数据表明它们还可以启动子血管重塑，使得这将如何影响 UPR激活。由于UPR导致促血管生成的转录和加工增加 因素，必须了解抗血管生成剂对UPR的影响，并确定是否是否 UPR在对这些药物的抵抗中起作用。在此提案中，我们描述了确定的实验 UPR提高对某些药物的敏感性的同时降低对其他药物的敏感性的机制， 探索与其他化学治疗剂的可能相互作用，并确定UPR的影响 动物模型中药物敏感性的激活。此外，我们将扩展对UPR的初步检查 在肿瘤样品中激活其他UPR靶标和多种类型的肿瘤以建立范围 我们对小儿癌的发现的意义。