Membrane Research Group of the Hungarian Academy of Sciences, Department of Biophysics, Semmelweis University and National Blood Center, Budapest, Hungary.
Biochem Biophys Res Commun. 2012 Apr 20;420(4):869-74. doi: 10.1016/j.bbrc.2012.03.090. Epub 2012 Mar 24.
The ATP-binding cassette (ABC) transporter ABCG2 plays an important role in tissue detoxification and confers multidrug resistance to cancer cells. Identification of expressional and functional cellular regulators of this multidrug transporter is therefore intensively pursued. The PI3-kinase/Akt signaling axis has been implicated as a key element in regulating various cellular functions, including the expression and plasma membrane localization of ABCG2. Here we demonstrate that besides inhibiting their respective target kinases, the pharmacological PI3-kinase inhibitor LY294002 and the downstream mTOR kinase inhibitor rapamycin also directly inhibit ABCG2 function. In contrast, wortmannin, another commonly used pharmacological inhibitor of PI3-kinase does not interact with the transporter. We suggest that direct functional modulation of ABCG2 should be taken into consideration when pharmacological agents are applied to dissect the specific role of PI3-kinase/Akt/mTOR signaling in cellular functions.
三磷酸腺苷结合盒（ABC）转运体 ABCG2 在组织解毒中发挥重要作用，并赋予癌细胞多药耐药性。因此，人们正在积极寻找这种多药转运蛋白表达和功能的细胞调节因子。PI3-激酶/Akt 信号通路已被认为是调节各种细胞功能的关键因素，包括 ABCG2 的表达和质膜定位。在这里，我们证明除了抑制各自的靶激酶外，药理学 PI3-激酶抑制剂 LY294002 和下游 mTOR 激酶抑制剂雷帕霉素也直接抑制 ABCG2 功能。相比之下，另一种常用的 PI3-激酶药理学抑制剂wortmannin 与转运体没有相互作用。我们建议，在应用药理学药物来剖析 PI3-激酶/Akt/mTOR 信号在细胞功能中的特定作用时，应考虑直接调节 ABCG2 的功能。
