ABC Transporters in Cancer and Other Diseases

在使用化疗剂治疗癌症患者的过程中，对多种抗癌剂具有抗性的肿瘤细胞的出现造成了严重的问题。在癌细胞中获得这种多药耐药表型通常与由多药耐药1（MDR 1）基因编码的细胞表面P-糖蛋白（P-gp）的表达增加相关，所述多药耐药1（MDR 1）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，也经常观察到非P-gp介导的多药耐药。在本研究中，我们鉴定并确定了cMOAT/MRP 2和MRP 3基因的核苷酸序列。然后通过cDNA转染实验发现这些基因分别参与了对长春新碱、顺铂、阿霉素和甲氨蝶呤以及足叶乙甙和甲氨蝶呤的耐药。我们还发现，癌细胞中MDR 1基因的过表达是由不同的机制触发的，例如CpG去甲基化、Alu介导的基因重排以及不同癌症类型中转录因子YB-1的移位。这些ATP结合盒（ABC）转运蛋白除了具有耐药性外，还具有重要的生理功能。我们在Dubin-Johnson综合征（人结合型高胆红素血症）中发现了4个cMOAT/MRP 2基因突变，提示cMOAT/MRP 2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功能。

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.