Copper metabolism as a unique vulnerability in cancer

铜代谢是癌症的独特弱点

• 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
• 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

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(申请人提供)：我们研究的目的是阐明ATP7A铜转运体在肿瘤生长和顺铂耐药的营养和代谢过程中的生物学作用。癌细胞的一个特征是营养代谢的潜在偏差，这一特征允许有效地结合营养以支持异常的增殖和转移。了解限制肿瘤生长和转移的营养物质运输途径在开发优先杀死肿瘤细胞的酶抑制剂方面越来越被认为是至关重要的。铜是一种必需的微量元素，在所有需氧生物的生物化学中起着基础性的作用。遗传性铜代谢紊乱，门克斯病，揭示了受影响的蛋白ATP7A在细胞铜稳态中的重要性。ATP7A不仅作为铜的输出者，从而防止细胞铜中毒，而且还将铜输送到分泌途径中的关键酶。一组被认为依赖于ATP7A的铜辅助因子的分泌酶包括赖氨酰氧化酶蛋白质家族(LOX和LOXL1-4)。这些蛋白质在肿瘤生长和转移中发挥关键作用，突出了铜稳态与癌症之间的独特联系，并强调了先验地抑制ATP7A作为防止LOX介导的癌症通路的可能性。此外，研究表明，ATP7A铜转运体在保护细胞免受顺铂的影响方面也很重要，顺铂是一种用于治疗多种癌症的化疗药物。因此，我们认为ATP7A可以作为肿瘤治疗的靶点，不仅可以防止肿瘤生长，还可以加强顺铂的化疗。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形成，这也使这些细胞对顺铂化疗敏感。此外，在原位乳腺癌的4T1细胞模型中，RNAi介导的ATP7A沉默阻止了原发肿瘤的生长，并显著抑制了继发的肺转移。目前提案中概述的研究试图阐明ATP7A在癌症生长和化疗耐药中的作用，从而阐明其作为治疗靶点的潜力。