Cellular folate status modulates the expression of BCRP and MRP multidrug transporters in cancer cell lines from different origins
Cellular folate status modulates the expression of BCRP and MRP multidrug transporters in cancer cell lines from different origins
复制标题
DOI：
10.1158/1535-7163.mct-08-0768
复制
发表时间：
2009-03-01
影响因子：
5.7
通讯作者：
Peters, Godefridus J.
中科院分区：
文献类型：
--
作者：
Lemos, Clara;Kathmann, Letje;Peters, Godefridus J.
由于细胞叶酸水平似乎对不同来源的癌细胞有不同的影响，我们将最初的研究扩展到更广泛的癌细胞组。在KB、OVCAR-3、IGF 3 -1、ZR 75 -1/R/MTX、SCC-11 B、SCC-22 B和WiDr中测定BCRP和MRP 1 -5表达，这些细胞生长在含2.3 μ mol/L超生理浓度叶酸[高叶酸（HF）]的标准RPMI 1640中，或适应于更高的生理浓度[1-5 nmol/L叶酸或亚叶酸;低叶酸（LF）]。与HF对应物相比，KB LF细胞显示MRP 3增加16.1倍，OVCAR-3 LF细胞显示MRP 4 mRNA水平沿着增加，同时MRP 3和MRP 4蛋白表达分别增加4.8倍。在WiDr LF细胞中观察到BCRP蛋白和mRNA表达的显著增加。与HF细胞系相比，这些细胞获得了类似于2倍的米托蒽醌耐药性，这是一种可被BCRP抑制剂Ko 143逆转的表型。值得注意的是，WiDr细胞在细胞内室中表达BCRP，与我们对Caco-2细胞的描述相似。我们的研究结果提供了进一步的证据，细胞叶酸状态的重要作用，在肿瘤细胞中的多药耐药转运蛋白的表达的调制。我们发现，上调细胞内定位的BCRP适应LF条件可能是一个共同的特点，在一组结肠癌细胞系。在这些情况下，叶酸补充可能通过降低BCRP表达来改善化疗药物的疗效。[Mol癌症治疗2009;8（3）：655 - 64]
As cellular folate levels seem to have a different effect on cancer cells from different origins, we extended our initial study to a broader panel of cancer cells. BCRP and MRP1-5 expression was determined in KB, OVCAR-3, IGROV-1, ZR75-1/R/MTX, SCC-11B, SCC-22B, and WiDr either grown in standard RPMI 1640 containing 2.3 mu mol/L supraphysiologic concentration of folic acid [high folate (HF)] or adapted to more physiologic concentrations [1-5 nmol/L folic acid or leucovorin; low folate (LF)]. Compared with the HF counterparts, KB LF cells displayed 16.1-fold increased MRP3 and OVCAR-3 LF cells showed 4.8-fold increased MRP4 mRNA levels along with increased MRP3 and MRP4 protein expression, respectively. A marked increase on BCRP protein and mRNA expression was observed in WiDr LF cells. These cells acquired similar to 2-fold resistance to mitoxantrone compared with the HF cell line, a phenotype that could be reverted by the BCRP inhibitor Ko143. Of note, WiDr cells expressed BCRP in the intracellular compartment, similarly to what we have described for Caco-2 cells. Our results provide further evidence for an important role of cellular folate status in the modulation of the expression of multidrug resistance transporters in cancer cells. We show that up-regulation of intracellularly localized BCRP in response to adaptation to LF conditions may be a common feature within a panel of colon cancer cell lines. Under these circumstances, folate supplementation might improve the efficacy of chemotherapeutic drugs by decreasing BCRP expression. [Mol Cancer Ther 2009;8(3):655 - 64]