UDP-glucuronosyltransferase 1A6 overexpression in breast cancer cells resistant to methotrexate
UDP-glucuronosyltransferase 1A6 overexpression in breast cancer cells resistant to methotrexate
复制标题
DOI：
10.1016/j.bcp.2010.09.008
复制
发表时间：
2011-01-01
影响因子：
5.8
通讯作者：
Ciudad, Carlos J.
中科院分区：
文献类型：
--
作者：
Cristina de Almagro, M.;Selga, Elisabet;Ciudad, Carlos J.
甲氨蝶呤是一种用于乳腺癌治疗的化疗药物，但耐药性的出现限制了其治疗用途。对敏感和甲氨蝶呤耐药的 MCF7 和 MDA-MB-468 乳腺癌细胞进行的微阵列分析指出，UDP-葡萄糖醛酸基转移酶 1A (UGT1A) 家族是这两种细胞系中常见的失调节点。该基因家族参与第二阶段代谢。 UGT1A6 是导致 UGT1A 家族在这些细胞中过度表达的主要亚型。它的过度表达并不是由于基因扩增。在敏感细胞中转染编码 UGT1A6 的载体可以抵消甲氨蝶呤引起的细胞毒性。甲氨蝶呤增加由 UGT1A6 启动子驱动的荧光素酶报告基因的转录活性，并诱导 UGT1A6 mRNA 和酶活性。启动子分析表明甲氨蝶呤对 UGT1A6 的诱导可能是由转录因子 ARNT (HIF-1) 和 AhR/ARNT 驱动的。由于 UGT1A6 的诱导，与对葡萄糖醛酸化敏感的抗癌药物（例如他莫昔芬或伊立替康）以及甲氨蝶呤一起孵育的细胞显示出较低程度的细胞毒性。当甲氨蝶呤与其他葡萄糖醛酸化药物联合使用时，应考虑这种诱导的药理作用。 (C) 2010 Elsevier Inc. 保留所有权利。
Methotrexate is a chemotherapeutic agent used in breast cancer treatment, but the occurrence of resistance limits its therapeutic use. A microarrays analysis between sensitive and methotrexate resistant MCF7 and MDA-MB-468 breast cancer cells pointed out the UDP-glucuronosyltransferase 1A (UGT1A) family as a common deregulated node in both cell lines. This family of genes is involved in Phase II metabolism. UGT1A6 was the main isoforrn responsible for UGT1A family overexpression in these cells. Its overexpression was not due to gene amplification. Transfection of a vector encoding for UGT1A6 in sensitive cells counteracted the cytotoxicity caused by methotrexate. Methotrexate increased the transcriptional activity from a luciferase reporter driven by the UGT1A6 promoter and induced UGT1A6 mRNA and enzymatic activity. Promoter analysis suggested that UGT1A6 induction by methotrexate could be driven by the transcription factors ARNT (HIF-1) and AhR/ARNT. Cells incubated with anticancer drugs susceptible to glucuronidation, such as tamoxifen or irinotecan, together with methotrexate, showed a lesser degree of cytotoxicity, due to UGT1A6 induction. The pharmacological effect of this induction should be taken into account when combining methotrexate with other drugs that are glucuronidated. (C) 2010 Elsevier Inc. All rights reserved.