Abstract 1080: Computational and biochemical discovery of RSK2 as a novel target for epigallocatechin gallate (EGCG)

The most active anticancer component in green tea is epigallocatechin-3-gallate (EGCG). Protein interaction with EGCG is a critical step mediating the effects of EGCG on the regulation of various key proteins involved in signal transduction. By using computational docking screening methods for protein identification, we identified a serine/threonine kinase, 90-kDa ribosomal S6 kinase (RSK2), as a novel molecular target of EGCG. RSK2 includes two kinase catalytic domains in the N-terminal (NTD) and the C-terminal (CTD) and its activation requires phosphorylation of both the NTD and CTD. The computer prediction was confirmed by an in vitro kinase assay in which EGCG inhibited RSK2 activity in a dose-dependent manner. Pull-down assay results showed that EGCG could bind with RSK2 at both kinase catalytic domains in vitro and ex vivo. Furthermore, results of an ATP competition assay and a computer-docking model showed that EGCG binds with RSK2 in an ATP-dependent manner. In RSK2+/+ and RSK2-/- murine embryonic fibroblasts, EGCG decreased viability only in the presence of RSK2. EGCG also suppressed epidermal growth factor-induced neoplastic cell transformation by inhibiting histone H3 Ser10 phosphorylation. Overall, these results indicate that EGCG is a novel natural compound for suppressing RSK2 kinase activity. Citation Format: Hanyong Chen, Ke Yao, Xiaoyu Chang, Jung-Hyun Shim, Hong-Gyum Kim, Margarita Malakhova, Dong-Joon Kim, Ann M. Bode, Zigang Dong. Computational and biochemical discovery of RSK2 as a novel target for epigallocatechin gallate (EGCG). [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1080. doi:10.1158/1538-7445.AM2015-1080