期刊
EBIOMEDICINE
卷 20, 期 -, 页码 79-97出版社
ELSEVIER
DOI: 10.1016/j.ebiom.2017.04.015
关键词
Atypical kinase; RIOK1; RAS T; hree-dimensional (3D) tissue culture; Xenografts; Bioluminescence imaging
资金
- Deutsche Forschungsgemeinschaft [CRC 850]
- Spemann Graduate School of Biology and Medicine (SGBM) [GSC-4]
- Excellence Initiative of the German Federal and State Governments through BIOSS [EXC 294]
- Emmy-Noether and Heisenberg programs of the Deutsche Forschungsgemeinschaft (DFG) [BR 3662/1, BR 3662/2]
Despite being overexpressed in different tumor entities, RIO kinases are hardly characterized in mammalian cells. We investigated the role of these atypical kinases in different cancer cells. Using isogenic colon-, breast-and lung cancer cell lines, we demonstrate that knockdown of RIOK1, but not of RIOK2 or RIOK3, strongly impairs proliferation and invasiveness in conventional and 3D culture systems. Interestingly, these effects were mainly observed in RAS mutant cancer cells. In contrast, growth of RAS wildtype Caco-2 and Bcr-Abl-driven K562 cells is not affected by RIOK1 knockdown, suggesting a specific requirement for RIOK1 in the context of oncogenic RAS signaling. Furthermore, we show that RIOK1 activates NF-kappa B signaling and promotes cell cycle progression. Using proteomics, we identified the pro-invasive proteins Metadherin and Stathmin1 to be regulated by RIOK1. Additionally, we demonstrate that RIOK1 promotes lung colonization in vivo and that RIOK1 is overexpressed in different subtypes of human lung-and breast cancer. Altogether, our data suggest RIOK1 as a potential therapeutic target, especially in RAS-driven cancers. (C) 2017 The Authors. Published by Elsevier B.V.
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