摘要
尽管癌症的多重耐药性已经广为人知,但是很少有人知道细胞通路调节MDR外排性转运体例如BCRP(ABCG2)的表达和转运。这里我们评估了EGFR的下游信号在BCRP表达和用于肺癌细胞存储的BCRP除了表达不同的EGFR和Ras激活变异亚细胞定位;A549 (K-Ras-G12S), H292 野生型 EGFR 和 Ras 及 H1650 (EGFR-DelE747-A750)。免疫细胞化学和免疫荧光研究证明了BCRP主要存在于细胞内,但是它的表达伴随着Ras激活和EGFR也被发现在A549和H1650细胞的细胞质膜内。值得注意的是,由埃罗替尼在IC50浓度下EGFR抑制剂诱导了一个特异的时间依赖性的BCRP基因改变和蛋白表达。在H1650细胞中,埃罗替尼通过泛素化作用在6-24小时内增强了BCRP的综述和细胞质膜的退化,而BCRP的表达在48小时后恢复原来的基础水平。埃罗替尼治疗的H292细胞,BCRP含量在24到72小时后降低;而在A549细胞,埃罗替尼最初降低BCRP的表达但是在72小时开始诱导其在质膜上的积累。我们进一步发现了PI3K/Akt抑制剂LY294002下调BCRP的表达,因此表明一种蛋白激酶通路参与了BCRP表达的调节,但是并不定位于这些肺癌细胞系中。最终,选择性BCRP运输抑制剂Ko143没有增加埃罗替尼的敏感性,但是因为它诱导它的转运基质拓扑替康的积累,从而降低BCRP在A549和H1650细胞中的运输活性。总之,我们的结果表明,表皮生长因子受体和一种蛋白激酶通路参与了BCRP表达、运输和药物转运活性的调节。这些发现确保了未来的研究在这些通路的药物调制来提高埃罗替尼和其他药物例如BCRP转运基质的抗癌药物组合的功效。
关键词: BCRP,化疗,EGFR,埃罗替尼,突变,Ras,泛素化
Current Drug Targets
Title:The EGFR Pathway Regulates BCRP Expression in NSCLC Cells: Role of Erlotinib
Volume: 15 Issue: 14
Author(s): Letizia Porcelli, Elisa Giovannetti, Yehuda G. Assaraf, Gerrit Jansen, George L. Scheffer, Ietje Kathman, Amalia Azzariti, Angelo Paradiso and Godefridus J. Peters
Affiliation:
关键词: BCRP,化疗,EGFR,埃罗替尼,突变,Ras,泛素化
摘要: While multidrug resistance (MDR) in cancer is well established, little is known about the cellular pathways regulating the expression and trafficking of the MDR efflux transporter like BCRP (ABCG2). Here we evaluated the role of signalling downstream of EGFR on BCRP expression and sub-cellular localization using lung cancer cells harboring BCRP but expressing various EGFR and Ras activating mutations; A549 (K-Ras-G12S), H292 wild-type EGFR and Ras, and H1650 (EGFR-DelE747-A750). Immunocytochemistry and immunofluorescence studies demonstrated that BCRP was predominantly intracellular but its expression was found also on the plasma membrane in A549 and H1650 cells with activated Ras and EGFR. Remarkably, EGFR inhibition by erlotinib at IC50 concentrations induced a differential timedependent alteration in BCRP gene and protein expression. In H1650 cells, erlotinib enhanced both the total and plasma membrane degradation of BCRP by ubiquitination within 6-24 hours, whereas BCRP expression regained the original basal levels after 48 hours. In erlotinib treated H292 cells, BCRP levels decreased at 24 hours until 72 hours, whereas in A549 cells erlotinib initially reduced BCRP expression but then induced its accumulation on the plasma membrane at 72 hours. We further found that the PI3K/Akt inhibitor LY294002 down-regulated BCRP expression, hence showing that the Akt pathway is involved in the regulation of BCRP expression but not in its localization in these lung cancer cell lines. Finally, the selective BCRP transport inhibitor Ko143 did not increase erlotinib sensitivity, but did decrease the transport activity of BCRP in A549 and H1650 cells as it induced the accumulation of its transport substrate topotecan. In conclusion, our results suggest that the EGFR and Akt pathways are involved in regulation of BCRP expression, trafficking and drug transport activity. These findings warrant future studies on the pharmacologic modulation of these pathways to enhance the efficacy of anticancer combinations of erlotinib with drugs that are BCRP transport substrates.
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Letizia Porcelli , Elisa Giovannetti , Yehuda G. Assaraf , Gerrit Jansen , George L. Scheffer , Ietje Kathman , Amalia Azzariti , Angelo Paradiso and Godefridus J. Peters , The EGFR Pathway Regulates BCRP Expression in NSCLC Cells: Role of Erlotinib, Current Drug Targets 2014; 15 (14) . https://dx.doi.org/10.2174/1389450116666141205145620
DOI https://dx.doi.org/10.2174/1389450116666141205145620 |
Print ISSN 1389-4501 |
Publisher Name Bentham Science Publisher |
Online ISSN 1873-5592 |
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