ABC Transporters in Cancer and Other Diseases

肿瘤细胞对多种抗癌药物耐药的出现是化疗药物治疗癌症患者的一个严重问题。在癌细胞中获得这种多药耐药表型通常与多药耐药基因(MDR1)编码的细胞表面P-糖蛋白(P-gp)表达增加有关，MDR1基因作为药物外排泵发挥作用，从而降低细胞内药物浓度。然而，非P-gp介导的多药耐药也经常被观察到。在本研究中，我们鉴定并测定了cMOAT/MRP2和MRP3基因的核苷酸序列。通过基因转染实验，发现这些基因分别参与了长春新碱、顺铂、阿霉素和甲氨蝶呤以及依托泊苷和甲氨蝶呤的耐药。我们还发现，在不同的癌症类型中，mdr1基因的过度表达是由不同的机制触发的，如CpG去甲基化、Alu介导的基因重排和转导因子YB-1的易位。除了多药耐药外，这些三磷酸腺苷结合盒(ABC)转运体还具有重要的生理功能。我们在人高结合胆红素血症Dubin-Johnson综合征中发现了cMOAT/MRP2基因的四个突变，提示cMOAT/MRP2基因在内源性和外源性阴离子结合物从肝细胞转移到胆汁中的作用。

The appearance of tumor cells resistant to multiple anticancer agents poses a serious problem during treatment of cancer patients using chemotherapeutic agents. The acquisition of such a multidrug resistance phenotype in cancer cells is often associated with increased expression of cell surface P-glycoprotein(P-gp) encoded by the multidrug resistance 1 (MDR1) gene that functions as a drug efflux pump, and thereby reduces the intracellular concentration of drugs. However, non-P-gp-mediated multidrug resistance is also frequently observed. In the present study, we identified and determined the nucleotide sequence of the cMOAT/MRP2 and MRP3 genes. We then found the participation of the genes on the drug resistance to vincristine, cisplatin, doxorubicin and methotrexate, and etoposide and methotrexate, respectively, by transfection experiment of the cDNAs. We also found that the overexpression of the MDR1 gene in cancer cells was trigared by different mechanisms such as CpG de-methylation, Alu-mediated gene rearrangement and translocation of the transcrptional factor YB-1 among different cancer type. Besides the multidrug resistance, these ATP binding cassette (ABC) transporters have important phisiological functions. We identified four mutations in cMOAT/MRP2 gene in Dubin-Johnson syndrome, human conjugated hyperbilirubinemia, suggesting the function of the cMOAT/MRP2 gene in the transfer of endogenous and exogenous anionic conjugates from hepatocytes into the bile.