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

• 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
• 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' -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

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）：细胞应激传感途径有助于适应不利的肿瘤微环境条件（例如营养缺乏、酸中毒和缺氧）并获得新的恶性特性。在此背景下，Hsp 90家族的分子伴侣是结癌基因，控制参与肿瘤细胞增殖、存活和适应应激的客户蛋白的折叠和成熟。Hsp 90（mtHsp 90）及其相关伴侣TRAP-1的线粒体库拮抗肿瘤细胞中的线粒体通透性转换并维持能量产生。我们小组的最新证据表明，mtHsp 90 s-定向的生物能量学对于拮抗巨自噬和调节细胞器未折叠蛋白反应（UPR）是必不可少的，该反应导致肿瘤细胞中基因表达的深度补偿性重塑。自从加入Altieri实验室以来，我发现用一种选择性工程化的小分子抑制剂（加米替尼）靶向Hsp 90的伴侣ATP酶活性，以在线粒体中积累，抑制细胞运动激酶FAK和Src的激活，抑制细胞骨架动力学并抑制肿瘤细胞迁移和侵袭。我们假设线粒体Hsp 90是肿瘤转移的新调节因子。在本申请中，我们将研究自噬和UPR对线粒体Hsp 90调节肿瘤细胞细胞骨架动力学和运动性的作用，以及它们对体内转移性传播的贡献。在目的1中，我们建议阐明代谢应激下FAK激活和肿瘤细胞运动性中自噬起始复合物的mtHsp 90 s调节的分子要求。在目的2中，我们将研究UPR参与肿瘤细胞中mtHsp 90 s介导的细胞骨架动力学调节。在目标3中，我们将验证mtHsp 90在体内转移动物模型中的作用。我们的研究将验证线粒体Hsp 90调节肿瘤生物能量学对转移性疾病的重要性，长期目标是确定新的治疗靶点以防止癌症的转移性传播。这里提出的研究计划将拓宽我在多个调查领域的知识、批判性思维和整体背景训练 包括细胞生物学、生物化学、分子生物学和癌症生物学。我还将获得在细胞运动，UPR，肿瘤细胞侵袭和转移的动物模型，在体内研究的广泛的定量方法的宝贵的专业知识。我对这种训练机制的目标是整合所有这些新知识，并全面了解关键压力和代谢途径如何调节转移。通过完成我的培训计划的其他组成部分，我希望在规划，实施和交流我的研究成果方面变得非常称职，制定进行研究的专业责任，并学习成为独立调查员所必需的关键人际交往技能。总之，本申请有望支持我成功地成为一名负责任和富有成效的独立调查员。