Overexpression of cMOAT (MRP2/ABCC2) is associated with decreased formation of platinum-DNA adducts and decreased G2-arrest in melanoma cells resistant to cisplatin
Overexpression of cMOAT (MRP2/ABCC2) is associated with decreased formation of platinum-DNA adducts and decreased G2-arrest in melanoma cells resistant to cisplatin
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DOI：
10.1046/j.1523-1747.2003.12313.x
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发表时间：
2003-07-01
影响因子：
6.5
通讯作者：
Lage, H
中科院分区：
文献类型：
--
作者：
Liedert, B;Materna, V;Lage, H
对各种抗肿瘤剂的耐药性是黑素瘤临床管理中的常见观察结果。赋予这些不同耐药表型的生物学机制，包括对常用抗癌药物顺铂的耐药性，尚不清楚。为了阐明膜三磷酸腺苷结合盒转运蛋白cMOAT（小管多特异性阴离子转运蛋白）（MRP 2/ABCC 2）在黑色素瘤顺铂耐药性中的作用，分析了该蛋白在铂耐药细胞系MeWo CIS 1中的表达。顺铂耐药的黑色素瘤细胞在mRNA和蛋白水平上表现出明显的cMOAT过表达。这一观察结果伴随着减少铂诱导的链内交联形成的核DNA通过免疫细胞学测定。这种DNA铂化的减少伴随着典型的顺铂诱导的G（2）阻滞后加速重新进入细胞周期，以及对凋亡的抵抗。铂-DNA加合物的形成和消除动力学表明，铂耐药黑色素瘤细胞中Pt-d（GpG）加合物的DNA修复能力没有升高。顺铂耐药黑色素瘤细胞中铂-DNA加合物形成的减少反映了转运蛋白cMOAT的保护活性。总之，cMOAT的功能抑制可能是逆转人类黑色素瘤对铂类抗癌药物耐药性的一种有前途的策略。
Resistance to various anti-neoplastic agents is a common observation in clinical management of melanoma. The biologic mechanisms conferring these different drug-resistant phenotypes, including resistance against the commonly used anti-cancer drug cisplatin, are unclear. In order to elucidate the role of the membrane adenosine triphosphate binding cassette-transporter cMOAT (canalicular multispecific anion transporter) (MRP2/ABCC2) in cisplatin resistance of melanoma, the expression of this protein was analyzed in the platinum drug-resistant cell line MeWo CIS 1. Cisplatinresistant melanoma cells showed a distinct overexpression of cMOAT on mRNA and protein level. This observation was accompanied by a reduced formation of platinum-induced intrastrand cross-links in the nuclear DNA measured by an immunocytologic assay. This decrease in DNA platination was accompanied by an accelerated re-entry into the cell cycle after the typical cisplatin-induced G(2) arrest, and a resistance to undergo apoptosis. Kinetics of formation and elimination of platinum-DNA adducts suggest that the DNA repair capacity for Pt-d(GpG) adducts was not elevated in platinum drug-resistant melanoma cells. The decrease in platinum-DNA adduct formation in cisplatin-resistant melanoma cells was rather a reflection of the protecting activity of the transporter cMOAT. In conclusion, the functional inhibition of cMOAT might be a promising strategy in the reversal of resistance to platinum-based anti-cancer drugs in human melanoma.