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，肿瘤细胞存在于一个受损的微环境中