Abstract 992: Regulation of ABCG2 Lysosomal Degradation by Xanthines: Role of the PI3K/AKT Pathway.

Abstract ABCG2 confers multidrug resistance to a wide range of structurally unrelated chemotherapeutic drugs, often resulting in the failure of cancer chemotherapy. Accordingly, the downregulation of ABCG2 expression and/or function has been proposed as part of a regimen to improve cancer therapeutic efficacy. Previously, we have reported that a group of xanthines including caffeine, theophylline and dyphylline can dramatically decrease ABCG2 protein in drug resistant cells, causing a significant increase in the intracellular retention of ABCG2 substrates and sensitization of the cells to chemotherapeutic agents (Ding et al., Mol Pharmacol 81:328-337, 2012). This downregulation of ABCG2 is due to a selective acceleration of its lysosomal degradation by xanthines. We now show that xanthines induce the endocytosis and subsequent degradation of ABCG2. In addition, PI3K/AKT/mTORC1 signaling was found to be involved in mediating the effect of xanthines on ABCG2, since both caffeine and theophylline strongly inhibited activation of AKT and mTORC1, and inhibition of both AKT and mTORC1 mimicked the effect of xanthines on ABCG2. Furthermore, adenosine, a nucleoside vital for purine metabolism and energy homeostasis, fully reversed the downregulation effect of caffeine on ABCG2. Interestingly, this adenosine-mediated effect occurs intracellularly and independent of adenosine receptor signalling, identifying a novel mechanism whereby the xanthine-degradation of ABCG2 is influenced by intracellular levels of adenosine. Importantly, adenosine also blocked the lysosomal degradation of ABCG2 that was induced by PI3K/AKT inhibition, indicating that the adenosine-mediated intracellular events cross-talk with the PI3K/AKT pathway in regulating ABCG2 degradation. This study enhances our understanding of the regulation of ABCG2 internalization and degradation, and identifies new targets for the development of ABCG2 expression/function modulating agents for chemosensitization. Citation Format: Rui Ding, Barton A. Kamen, Jia Shi, Kathleen W. Scotto. Regulation of ABCG2 lysosomal degradation by xanthines: Role of the PI3K/AKT pathway. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 992. doi:10.1158/1538-7445.AM2013-992