FUNCTION OF THE MRP/CMOAT SUBFAMILY

MRP/CMOAT 子家族的功能

• 批准号: 2842068
• 负责人: Gary D Kruh
• 金额: $ 32.64万
• 依托单位: FOX CHASE CANCER CENTER
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-09-01 至 2002-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2842068
• 关键词: P glycoprotein; antineoplastics; chemosensitizing agent; cytotoxicity; drug resistance; embryonic stem cell; excretion; fluorescent dye /probe; gene expression; immunocytochemistry; kidney metabolism; laboratory mouse; laboratory rabbit; liver metabolism; membrane transport proteins; pharmacokinetics; protein structure function; tissue /cell culture; yeasts

Cellular resistance is the major obstacle to the successful treatment of disseminated malignancies. A fundamental resistance mechanism involves reducing cellular drug concentrations by pumping cytotoxic agents across the plasma membrane. P-glycoprotein, an ABC family transporter that confers resistance to several natural product drugs, was the first example of this mechanism. More recently MRP, an ABC transporter distantly related to Pgp, has been shown to confer a multidrug resistance phenotype that is similar but not identical to Pgp. In addition, increasing evidence indicates that a close relative of MRP, the canalicular multispecific organic anion transporter (cMOAT), confers resistance to both natural product drugs and cisplatin in cells in which it is induced. cMOAT, whose normal expression is restricted to liver canaliculi, has also been demonstrated to be involved in the hepatobiliary excretion of anticancer drugs such as methotrexate, by pumping these agents directly into the bile. Our laboratory has recently isolated four novel MRP/cMOAT-related transporters, designated MOAT-B, C, D and E. These four transporters, along with MRP and cMOAT, form a tight evolutionary cluster that defines the MRP/cMOAT subfamily. Analysis of the predicted structures of these four transporters reveals that D is the closest known relative of MRP (significantly more related to MRP than is cMOAT), and that E and cMOAT are about equally related to MRP. Expression of MOAT-D is primarily restricted to liver, kidney, colon and pancreas, and E is expressed only in the kidney and liver. These observations are highly suggestive that D and E are involved in both cellular resistance as well as the hepatobiliary and renal excretion of anticancer agents. While MOAT-B and MOAT-C are not as closely related to MRP as are D and E, they are part of the MRP/cMOAT evolutionary cluster, and may therefore also be involved in cellular resistance. The purpose of this proposal is to elucidate the roles of these novel MRP/cMOAT-related transporters in cellular resistance and hepatobiliary and renal excretion of anticancer agents. Elucidating their function will provide important information concerning the drug resistant phenotype and the pharmacokinetics of anticancer agents, and will impact the development of modulation strategies designed to circumvent membrane-based resistance mechanisms.

细胞耐药是成功治疗播散性恶性肿瘤的主要障碍。一种基本的耐药机制包括通过将细胞毒剂泵过质膜来降低细胞药物浓度。P-糖蛋白是这种机制的第一个例子，它是一种ABC家族转运蛋白，可以对几种天然产物药物产生抗药性。最近，与Pgp有远亲关系的ABC转运蛋白MRP被证明具有与Pgp相似但不完全相同的多药耐药表型。此外，越来越多的证据表明，MRP的近亲，管状多特异性有机阴离子转运体(CMOAT)，在诱导其产生的细胞中对天然产物药物和顺铂都具有耐药性。CMOAT的正常表达仅限于肝小管，也已被证明参与抗癌药物如甲氨蝶呤的肝胆排泄，通过将这些药物直接泵入胆汁中。我们实验室最近分离到了四个新的与MRP/cMOAT相关的转运蛋白，命名为Moat-B、C、D和E。这四个转运蛋白与MRP和cMOAT一起形成了一个紧密的进化簇，定义了MRP/cMOAT亚家族。对这四个转运蛋白预测结构的分析表明，D是已知的与MRP关系最密切的亲缘关系(与MRP的关系明显高于cMOAT)，而E和cMOAT与MRP的关系大致相同。MOAT-D主要在肝脏、肾脏、结肠和胰腺表达，而E仅在肾脏和肝脏表达。这些观察结果高度提示，D和E参与了细胞抵抗以及抗癌药物的肝胆和肾排泄。虽然MOAT-B和MOAT-C与MRP的关系不像D和E那么密切，但它们是MRP/cMOAT进化簇的一部分，因此也可能参与细胞耐药。本研究的目的是阐明这些新的MRP/cMOAT相关转运蛋白在细胞抵抗和抗癌药物的肝、胆、肾排泄中的作用。阐明它们的功能将提供有关抗癌药物耐药表型和药代动力学的重要信息，并将影响旨在绕过膜耐药机制的调控策略的发展。