Role of the mitochondrial ABC protein ABCB6 in drug resistance

线粒体ABC蛋白ABCB6在耐药性中的作用

• 批准号: 7418602
• 负责人: GERGELY SZAKACS
• 金额: $ 5.12万
• 依托单位: TERMESZETTUDOMANYI KUTATOKOZPONT
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-06-01 至 2011-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7418602
• 关键词: ABCB1 gene; ABCB6 gene; ATP Hydrolysis; ATP phosphohydrolase; ATP-Binding Cassette Transporters; ATP-Binding Cassette, Sub-Family B, Member 6; Address; Antibodies; Antimony; Antineoplastic Agents; Arsenic; Arsenites; Binding; Biochemical; Biochemistry; Biological Assay; C-terminal; Cancer Death Rates; Cell Fractionation; Cell Line; Cell membrane; Cell physiology; Cells; Centrifugation; Cessation of life; Cisplatin; Clinical; Collaborations; Complex; Confocal Microscopy; Cross-Linking Reagents; Cytotoxic agent; Detection; Diagnosis; Digitonin; Disseminated Malignant Neoplasm; Drug Metabolic Detoxication; Drug resistance; Effectiveness; Ensure; Epitopes; Family; Fibroblasts; Foundations; Fox Chase Cancer Center; Functional disorder; Genomics; Goals; Heavy Metals; Imaging Techniques; Immunoblotting; In Vitro; Insecta; Investigation; Knock-out; Laboratories; Life; Light; Link; Localized; Malignant Neoplasms; Mammalian Cell; Measurement; Measures; Mediating; Mediator of activation protein; Membrane; Mitochondria; Molecular; Monitor; Multi-Drug Resistance; Nature; Nucleotides; Organelles; P-Glycoprotein; Pharmaceutical Preparations; Pharmacogenomics; Philadelphia; Physiological; Play; Postdoctoral Fellow; Principal Investigator; Protein Overexpression; Proteins; Pump; Radioactive; Reporting; Research Personnel; Resistance; Role; Series; Students; Subcellular Fractions; System; Testing; Time; Tissues; Toxic effect; Transmembrane Domain; Variant; Vesicle; Work; analog; base; cancer cell; cell killing; chemotherapy; concept; cytotoxicity; design; experience; mitochondrial membrane; mouse model; multi drug transporter; novel; paraform; programs; protein aminoacid sequence; protein crosslink; research study; tool; trafficking

DESCRIPTION (provided by applicant): The ABC (ATP-Binding Cassette) family includes the best known mediators of resistance to anticancer drugs. In particular, MDR (multidrug resistance) pumps actively extrude many types of drugs from cancer cells, thereby conferring resistance to those agents. Arsenite is an increasingly used anticancer agent, while arsenic toxicity is an emerging problem all over the world. Our preliminary results indicate that, unexpectedly, the expression and function of ABCB6 may be an important cellular mechanism to provide arsenite resistance. Despite the established role of ABC transporters in detoxification, this concept remains challenging. ABCB1-MDR1 provides resistance by keeping the intracellular levels of various anticancer agents below a cell-killing threshold. ABCB6 is, however, expressed in the mitochondrial membrane, raising the question as to how its function may convey resistance to the cells. The overall goal of this proposal is to understand how mitochondrial ABC transporters provide drug resistance. The specific hypothesis to be tested is that ABCB6 plays a role in protecting the cells against arsenite-mediated toxicity. This hypothesis is based on the following observations: First, we found that cells selected for resistance to arsenite express higher levels of ABCB6 than parental lines; Second, the overexpression of ABCB6 conferred broad resistance to heavy metals; Third, a pharmacogenomic approach based on the analysis of the NCI60 cell panel suggested the involvement of ABCB6 in drug resistance. Based on these observations, a comprehensive series of studies is proposed to determine the biochemical mechanism by which ABCB6 confers resistance. In particular, the studies proposed are designed to address the following critical questions: First, what substrate(s) does ABCB6 transport? Second, where is ABCB6 located in the cell? Third, what is the functional form of ABCB6? Relevance Although considerable progress has been made in treating cancer over the past decade with a gradual decline in cancer death rates, there are still over 500,000 deaths from cancer in the U.S. each year. Effective treatment of most metastatic cancers requires the use of toxic chemotherapy. Unfortunately, cancer cells may become resistant against cytotoxic agents, often through the elevated activity of ABC transporters, which mediate the energy-dependent efflux of various drugs from cancer cells. This proposal's aim is to elucidate the mechanism and biochemistry of ABCB6, a candidate multidrug transporter.

描述（由申请人提供）：ABC（ATP结合盒）家族包括对抗癌药物抗药性的最著名介体。特别是，MDR（多药耐药性）泵积极地将许多类型的药物从癌细胞中挤出，从而赋予对这些药物的耐药性。砷是一种日益使用的抗癌剂，而砷的毒性是世界各地的新兴问题。我们的初步结果表明，出乎意料的是，ABCB6的表达和功能可能是提供砷耐药性的重要细胞机制。尽管ABC转运蛋白在排毒中起着确定的作用，但该概念仍然具​​有挑战性。 ABCB1-MDR1通过将各种抗癌药物的细胞内水平保持在细胞杀伤阈值以下。然而，在线粒体膜中表达了ABCB6，这提出了有关其功能如何传达对细胞的抗性的问题。该提案的总体目标是了解线粒体ABC转运蛋白如何提供耐药性。要测试的特定假设是ABCB6在保护细胞免受砷介导的毒性毒性中起作用。该假设基于以下观察结果：首先，我们发现选择用于抗砷的细胞表现出比亲本线更高的ABCB6水平。其次，ABCB6的过表达赋予了对重金属的广泛抗性。第三，基于NCI60细胞面板分析的药物基因组学方法表明，ABCB6参与耐药性。基于这些观察结果，提出了一系列全面的研究，以确定ABCB6赋予耐药性的生化机制。特别是，提出的研究旨在解决以下关键问题：首先，ABCB6运输是什么底物？其次，ABCB6在细胞中位于哪里？第三，ABCB6的功能形式是什么？尽管在过去的十年中，癌症死亡率逐渐下降，尽管在治疗癌症方面取得了长足的进展，但美国每年仍有超过500,000人死亡。有效治疗大多数转移性癌症需要使用有毒化疗。不幸的是，通常通过ABC转运蛋白的活性升高，癌细胞可能会抗细胞毒性剂，从而介导癌细胞的各种药物的能量依赖性外排。该提议的目的是阐明候选多药物转运蛋白ABCB6的机制和生物化学。