Analysis of ABCG2 expression and side population identifies intrinsic drug efflux in the HCC cell line MHCC-97L and its modulation by Akt signaling
Analysis of ABCG2 expression and side population identifies intrinsic drug efflux in the HCC cell line MHCC-97L and its modulation by Akt signaling
复制标题
DOI：
10.1093/carcin/bgn223
复制
发表时间：
2008-12-01
期刊：
影响因子：
4.7
通讯作者：
Gu, Jianren
中科院分区：
文献类型：
--
作者：
Hu, Chen;Li, Hong;Gu, Jianren
三磷酸腺苷结合盒（ABC）转运体ABCG2的主动药物外排是多种人类癌症产生多重耐药的常见机制之一。在肝细胞癌（HCC）的内在耐药性中，ABCG2的作用与“侧群（SP）”密切相关，侧群是一小部分癌症干细胞样细胞，具有独特的挤出亲脂性染料Hoechst 33342和许多化疗药物的能力。在这项研究中，我们发现ABCG2在HCC组织的一个亚群中内在表达，其表达模式显著影响HCC细胞系的药物外排水平。在固有ABCG2表达的MHCC-97L HCC细胞系中，我们证实了SP细胞在药物外排相关化疗耐药中的重要性，发现SP分析为评估ABCG2转运体的功能活性提供了一种有效的方法。在该细胞系中，我们发现Akt信号抑制剂和血清补充可以调节SP的比例，从而发现Akt信号可以通过改变ABCG2转运体的亚细胞定位来调节SP细胞的外排活性。我们进一步证明Akt信号抑制可减弱MHCC-97L细胞的阿霉素外排，提高药物疗效。我们的研究结果表明ABCG2内在表达在HCC细胞中的保护作用，并提示抑制Akt信号可以帮助克服ABCG2转运体的药物外泄。
Active drug efflux by the adenosine triphosphate-binding cassette (ABC) transporter ABCG2 is one of the common mechanisms causing multiple drug resistance in various human cancers. In the intrinsic drug resistance of hepatocellular carcinoma (HCC), the role of ABCG2 is closely associated with 'side population (SP)', a minor subset of cancer stem-like cells with unique capacity to extrude lipophilic dye Hoechst 33342 and many chemotherapeutic agents. In this study, we showed that ABCG2 was intrinsically expressed in a subgroup of HCC tissues and its expression pattern significantly influenced the levels of drug efflux from HCC cell lines. In MHCC-97L HCC cell line with intrinsic ABCG2 expression, we confirmed the importance of SP cells to the drug efflux-related chemotherapy resistance and found that the SP analysis provided an efficient method to evaluate the functional activity of ABCG2 transporter. In this cell line, we discovered that the SP proportion was modulated by the treatments of Akt signaling inhibitors and serum supplement, which led to the finding that Akt signaling was able to regulate the SP cells' efflux activity via altering the subcellular localization of ABCG2 transporter. We further demonstrated that the Akt signaling inhibition attenuated the doxorubicin efflux from MHCC-97L cells and increased the drug efficacy. Our results indicate the protective role of intrinsic ABCG2 expression in HCC cells and suggest that suppressing Akt signaling could help overcome the drug efflux by ABCG2 transporter.