Mitochondrial Hsp90s Regulation of Tumor Bioenergetics and Metastasis

线粒体 Hsp90s 对肿瘤生物能学和转移的调节

基本信息

批准号：
8520828
负责人：
Maria Cecilia Caino
金额：
$ 5.49万
依托单位：
WISTAR INSTITUTE
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-09-23 至 2016-09-22
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8520828
关键词：
5&apos -AMP-activated protein kinase ATP phosphohydrolase Acidosis Affect Animal Model Autophagocytosis Biochemical Biochemistry Bioenergetics Biological Assay Cancer Biology Cancer Patient Cancer cell line Catabolism Cell Proliferation Cell Survival Cells Cellular Stress Cellular Stress Response Cellular biology Client Communication Complex Cytoskeleton Development Disease Disseminated Malignant Neoplasm Endoplasmic Reticulum Engineering Environment Gene Expression Genes Goals Growth Heat-Shock Proteins 90 Human Hypoxia Investigation Knowledge Laboratories Learning Liver Lysosomes Malignant - descriptor Malignant Neoplasms Malignant neoplasm of lung Mediating Mediator of activation protein Metabolic Pathway Metabolic stress Metastatic Neoplasm to the Bone Metastatic to Mitochondria Modeling Molecular Molecular Biology Molecular Chaperones Molecular Structure Neoplasm Metastasis Nodal Nutrient Oncogenes Organelles Outcome Oxygen PTK2 gene Pathway interactions Permeability Pharmaceutical Preparations Phosphorylation Phosphotransferases Play Production Property Protein Biosynthesis Proteins Public Health Recycling Regulation Relative (related person)Research Research Personnel Role Signal Transduction Signaling Molecule Sirolimus Starvation Stress Structure Supporting Cell Thinking Time Training Tumor Cell Invasion Work advanced disease base cell growth cell motility coping deprivation detection of nutrient human FRAP1 protein in vivo inhibitor/antagonist lymph nodes molecular chaperone GRP78 mutant neoplastic cell new therapeutic target novel novel therapeutics prevent protein folding public health relevance research study response rho GTP-Binding Proteins skills small molecule trait tumor tumor microenvironment

项目摘要

DESCRIPTION (provided by applicant): Cellular stress sensing pathways contribute to adaptation to unfavorable tumor microenvironment conditions (e.g. nutrient deprivation, acidosis and hypoxia) and to the acquisition of new malignant properties. In this context, the molecular chaperones of the Hsp90 family are nodal cancer genes, controlling the folding and maturation of client proteins involved in tumor cell proliferation, survival and adaptation to stress. Mitochondrial pools of Hsp90 (mtHsp90) and its related chaperone, TRAP-1, antagonize mitochondrial permeability transition and maintain energy production in tumor cells. Recent evidences from our group indicate that mtHsp90s- directed bioenergetics is essential to antagonize macroautophagy and to regulate an organelle unfolded protein response (UPR) that leads to profound compensatory remodeling of gene expression in tumor cells. Since joining the Altieri laboratory, I found that targeting the chaperone ATPase activity of Hsp90s with a small molecule inhibitor selectively engineered to accumulate in mitochondria (Gamitrinib), suppressed activation of cell motility kinases FAK and Src, inhibited cytoskeletal dynamics and suppressed tumor cell migration and invasion. We hypothesize that mitochondrial Hsp90s are novel regulators of metastasis in tumors. In the present application we will investigate the role o autophagy and the UPR on mitochondrial Hsp90s regulation of tumor cell cytoskeletal dynamics and motility, and their contribution to metastatic dissemination in vivo. In Aim 1, we propose to elucidate the molecular requirements for mtHsp90s modulation of the autophagy initiating complex in FAK activation and tumor cell motility under metabolic stress. In Aim 2, we will study the involvement of the UPR in mtHsp90s-mediated regulation of cytoskeletal dynamics in tumor cells. In Aim 3, we will validate the role of mtHsp90s in animal models of metastasis in vivo. Our studies will verify the importance of the regulation of tumor bioenergetics by mitochondrial Hsp90s for metastatic disease, with the long term goal of identifying novel therapeutic targets to prevent the metastatic dissemination of cancer. The research plan proposed here will broaden my knowledge, critical thinking and overall background training in multiple fields of investigation including cell biology, biochemistry, molecular biology and cancer biology. I will also gain invaluable expertise in a broad range of quantitative approaches for the study of cell motility, UPR, tumor cell invasion and animals models of metastasis, in vivo. My goal for this training mechanism is to integrate all this new knowledge and formulate a comprehensive understanding of how key stress and metabolic pathways modulate metastasis. By completing the other components of my training plan I expect to become extremely competent in the planning, implementation and communication of my research results, develop a professional responsibility for conducting research, as well as learn key interpersonal skills essential to become an independent investigator. In summary, the present application is expected to support my successful establishment as a responsible and productive independent investigator.

描述（由申请人提供）：细胞应力感应途径有助于适应不利的肿瘤微环境条件（例如养分剥夺，酸中毒和缺氧），并有助于获得新的恶性特性。在这种情况下，HSP90家族的分子伴侣是淋巴结癌基因，可控制参与肿瘤细胞增殖，生存和适应应激的客户蛋白的折叠和成熟。 HSP90（MTHSP90）及其相关的伴侣TRAP-1的线粒体池拮抗线粒体通透性过渡并维持肿瘤细胞中的能量产生。我们组的最新证据表明，MTHSP90S定向的生物能学对于拮抗大噬菌学和调节细胞器展开的蛋白质反应（UPR）至关重要，该蛋白质反应（UPR）导致肿瘤细胞中基因表达的深刻补偿性重塑。自加入Altieri实验室以来，我发现针对HSP90S的伴侣ATPase活性，具有小分子抑制剂选择性地设计为在线粒体（Gamitrinib）中积累的工程，抑制细胞运动激酶FAK和SRC的激活，抑制细胞骨骼动力学和抑制细胞菌群细胞迁移和Invisasion。我们假设线粒体HSP90是肿瘤转移的新调节剂。在本应用中，我们将研究自噬的作用和UPR在线粒体HSP90S调节肿瘤细胞骨骼骨骼动力学和运动性的调节，以及它们对体内转移性传播的贡献。在AIM 1中，我们建议阐明在代谢应激下自噬启动复合物的MTHSP90调制和肿瘤细胞运动的调节。在AIM 2中，我们将研究UPR参与MTHSP90S介导的肿瘤细胞细胞骨架动力学调节。在AIM 3中，我们将验证MTHSP90在体内转移动物模型中的作用。我们的研究将验证线粒体HSP90对转移性疾病调节肿瘤生物能力的重要性，其长期目标是鉴定新的治疗靶标，以防止癌症的转移性传播。这里提出的研究计划将扩大我的知识，批判性思维和整体背景培训包括细胞生物学，生物化学，分子生物学和癌症生物学。在体内，我还将在研究细胞运动，UPR，肿瘤细胞侵袭和转移动物模型的多种定量方法中获得宝贵的专业知识。我的这种训练机制的目标是整合所有这些新知识，并对关键压力和代谢途径如何调节转移的全面理解。通过完成我的培训计划的其他组成部分，我希望在研究结果的计划，实施和沟通中具有极大的能力，从事进行研究的专业责任，并学习成为独立研究者必不可少的人际交往能力。总而言之，预计本申请将支持我作为负责任和富有成效的独立调查员的成功建立。