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: 7644452
• 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/7644452
• 关键词: ABCB1 gene; ABCB6 gene; ATP Hydrolysis; ATP phosphohydrolase; ATP-Binding Cassette Transporters; 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; Malignant Neoplasms; Mammalian Cell; Measurement; Measures; Mediating; Mediator of activation protein; Membrane; Mitochondria; Molecular; Monitor; Multi-Drug Resistance; Nature; Nucleotides; Organelles; Pharmaceutical Preparations; Pharmacogenomics; Philadelphia; Physiological; Play; Postdoctoral Fellow; Principal Investigator; Proteins; Pump; Radioactive; Reporting; Research Personnel; Resistance; Role; Series; Subcellular Fractions; System; Testing; Time; Tissues; Toxic effect; Transmembrane Domain; Variant; Vesicle; Work; analog; base; cancer cell; cell killing; chemotherapy; cytotoxicity; design; effective therapy; experience; graduate student; in vitro testing; mitochondrial membrane; mouse model; multi drug transporter; novel; overexpression; 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(申请人提供)：ABC(三磷酸腺苷结合盒)家族包括最知名的抗癌药物耐药介质。特别是，MDR(多药耐药)泵主动将多种类型的药物从癌细胞中排出，从而对这些药物产生耐药性。亚砷酸盐是一种应用越来越广泛的抗癌药物，而砷中毒是世界范围内出现的一个新问题。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亚砷酸盐抗性的一个重要的细胞机制。尽管ABC转运蛋白在解毒中的作用已经确立，但这一概念仍然具有挑战性。ABCB1-MDR1通过将各种抗癌剂的细胞内水平保持在细胞杀伤阈值以下来提供耐药性。然而，ABCB6在线粒体膜上表达，这引发了一个问题，即它的功能如何向细胞传递耐药性。这项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。需要检验的具体假设是ABCB6在保护细胞免受亚砷酸盐介导的毒性方面发挥作用。这一假说基于以下观察：第一，我们发现对亚砷酸盐具有抗性的细胞比亲本株表达更高水平的ABCB6；第二，ABCB6的过度表达赋予了对重金属的广泛耐药性；第三，基于NCI60细胞小组分析的药物基因组学方法表明ABCB6参与了耐药性。在这些观察的基础上，提出了一系列全面的研究，以确定ABCB6赋予抗性的生化机制。特别是，建议的研究旨在解决以下关键问题：第一，ABCB6运输什么底物(S)？其次，ABCB6在细胞中的位置是什么？第三，ABCB6的功能形式是什么？相关性尽管在过去十年中，癌症的治疗取得了长足的进步，癌症死亡率逐渐下降，但美国每年仍有超过50万人死于癌症。大多数转移性癌症的有效治疗需要使用毒性化疗。不幸的是，癌细胞可能会对细胞毒剂产生抗药性，这通常是通过ABC转运蛋白的活性升高来实现的，ABC转运蛋白介导了多种药物从癌细胞中依赖能量的外流。这项提议的目的是阐明ABCB6的机制和生化，ABCB6是一种候选的多药转运体。