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

基本信息

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
项目类别：
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

项目摘要

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）家族包括最著名的抗癌药物耐药性介质。特别是，MDR（多药耐药性）泵主动从癌细胞中挤出多种类型的药物，从而赋予这些药物耐药性。亚砷酸盐是一种越来越多使用的抗癌剂，而砷毒性是世界各地一个新出现的问题。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重要细胞机制。尽管 ABC 转运蛋白在解毒中的作用已被确定，但这一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来提供耐药性。然而，ABCB6 在线粒体膜中表达，这就提出了其功能如何向细胞传递抗性的问题。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。这一假设基于以下观察：首先，我们发现选择抗亚砷酸盐的细胞比亲本系表达更高水平的 ABCB6；其次，ABCB6的过度表达赋予了对重金属的广泛抵抗力；第三，基于NCI60细胞组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来确定 ABCB6 赋予耐药性的生化机制。特别是，所提出的研究旨在解决以下关键问题：首先，ABCB6 运输什么底物？其次，ABCB6 位于细胞中的什么位置？第三，ABCB6的函数形式是什么？相关性尽管过去十年在癌症治疗方面取得了相当大的进展，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有毒化疗。不幸的是，癌细胞可能会对细胞毒性药物产生耐药性，这通常是通过 ABC 转运蛋白活性的升高来实现的，ABC 转运蛋白介导癌细胞中各种药物的能量依赖性流出。该提案的目的是阐明 ABCB6（一种候选多药转运蛋白）的机制和生物化学。