Copper metabolism as a unique vulnerability in cancer

铜代谢是癌症的独特弱点

基本信息

批准号：
9178063
负责人：
MICHAEL J. PETRIS
金额：
$ 34.52万
依托单位：
UNIVERSITY OF MISSOURI-COLUMBIA
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-12-01 至 2019-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9178063
关键词：
4T1 ATP phosphohydrolase ATP7A protein Aerobic Affect Biochemical Biochemistry Biological Breast Carcinoma Cell membrane Cell model Cells Cisplatin Connective Tissue Copper Cultured Cells Cytoplasm Data Defect Development Disease Drug resistance E-Cadherin Enzyme Inhibitor Drugs Enzymes Fibroblasts Foundations Genes Genetic Transcription Goals Growth Homeostasis Human Hypersensitivity In Vitro Inborn Genetic Diseases LOX gene Malignant Neoplasms Mediating Menkes Kinky Hair Syndrome Metabolism Metastatic Carcinoma Metastatic Neoplasm to the Lung Modeling Mus Mutate Neoplasm Metastasis Nude Mice Nutrient Nutritional Organism Pathway interactions Platinum Play Primary Neoplasm Protein Family Protein-Lysine 6-Oxidase Proteins RNA Interference Resistance Role Solid Testing Toxic effect Trace Elements Tumorigenicity Vesicle Wilson disease protein Work amine oxidase base cancer cell cancer therapy cell motility chemotherapy cofactor cytotoxicity epithelial to mesenchymal transition in vivo infancy killings member neoplastic cell novel nutrient metabolism prevent public health relevance skeletal tissue therapeutic target trans-Golgi Network transcription factor tumor tumor growth tumorigenesis tumorigenic

项目摘要

DESCRIPTION (provided by applicant): The objectives of our studies are to elucidate the biological roles of the ATP7A copper transporter in the nutritional and metabolic processes of tumor growth and resistance against cisplatin chemotherapy. A hallmark of cancer cells is an underlying deviation in nutrient metabolism, a feature that permits efficient incorporation of nutrients to support abnormal proliferation and metastasis. Understanding the pathways of nutrient transport that are rate limiting for tumor growth and metastasis is increasingly recognized as critical in the development of enzyme inhibitors that will preferentially kill tumor cells. Copper is an essential trace element that plays a fundamental role in the biochemistry of all aerobic organisms. The inherited disorder of copper metabolism, Menkes disease, has revealed the importance of the affected protein ATP7A in cellular copper homeostasis. ATP7A functions not only as an exporter of copper, thus preventing cellular copper toxicity, but also in the delivery of copper to critical enzymes in the secretory pathway. A group of secreted enzymes that are thought to rely on ATP7A for their copper cofactor include the lysyl oxidase family of proteins (LOX and LOXL1-4). These proteins play key roles in tumor growth and metastasis, highlighting a unique connection between copper homeostasis and cancer, and underscoring a priori the potential to inhibit ATP7A as a means to prevent LOX-mediated pathways in cancer. Furthermore, studies suggest that the ATP7A copper transporter is also important in protecting cells against cisplatin, a chemotherapy agent used to treat a wide variety of cancers. Thus, we propose that ATP7A could be exploited as a target in cancer treatment not only to prevent tumor growth, but also to potentiate cisplatin chemotherapy. In support of this hypothesis, our preliminary results demonstrate that tumorigenesis of RAS-transformed fibroblasts was inhibited by deletion of the ATP7A gene, which also rendered these cells hypersensitive to cisplatin chemotherapy. Additionally, RNAi-mediated silencing of ATP7A in the 4T1 cell model of orthotopic breast carcinoma blocked primary tumor growth and markedly inhibited secondary lung metastasis. The studies outlined in the current proposal seek to elucidate the roles of ATP7A in both cancer growth and chemotherapy drug resistance, and thus its potential as a therapeutic target.

描述（由申请人提供）：我们研究的目的是阐明 ATP7A 铜转运蛋白在肿瘤生长和顺铂化疗耐药的营养和代谢过程中的生物学作用。癌细胞的一个标志是营养代谢的潜在偏差，这一特征允许有效地掺入营养物质以支持异常增殖和转移。人们越来越认识到，了解限制肿瘤生长和转移速率的营养物质运输途径对于开发优先杀死肿瘤细胞的酶抑制剂至关重要。铜是一种必需的微量元素，在所有需氧生物的生物化学中发挥着重要作用。铜代谢的遗传性疾病门克斯病揭示了受影响的蛋白质 ATP7A 在细胞铜稳态中的重要性。 ATP7A 不仅充当铜的输出者，从而防止细胞铜毒性，而且还将铜传递给分泌途径中的关键酶。一组被认为依赖 ATP7A 提供铜辅因子的分泌酶包括赖氨酰氧化酶蛋白家族（LOX 和 LOXL1-4）。这些蛋白质在肿瘤生长和转移中发挥着关键作用，凸显了铜稳态与癌症之间的独特联系，并强调了抑制 ATP7A 作为预防癌症中 LOX 介导途径的一种手段的潜力。此外，研究表明 ATP7A 铜转运蛋白对于保护细胞免受顺铂（一种用于治疗多种癌症的化疗药物）的侵害也很重要。因此，我们提出 ATP7A 可以作为癌症治疗的靶点，不仅可以预防肿瘤生长，还可以增强顺铂化疗的效果。为了支持这一假设，我们的初步结果表明，ATP7A 基因的缺失抑制了 RAS 转化的成纤维细胞的肿瘤发生，这也使得这些细胞对顺铂化疗过敏。此外，在原位乳腺癌4T1细胞模型中，RNAi介导的ATP7A沉默可阻断原发性肿瘤生长并显着抑制继发性肺转移。当前提案中概述的研究旨在阐明 ATP7A 在癌症生长和化疗耐药性中的作用，从而阐明其作为治疗靶点的潜力。