The Atypical Kinase RIOK1 Promotes Tumor Growth and Invasive Behavior

Abstract

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-κB 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.

RIOK2 is negatively regulated by miR‐4744 and promotes glioma cell migration/invasion through epithelial‐mesenchymal transition

“…Recently, emerging evidence has suggested an important role of RIO kinases in tumour development and expansion beyond ribosomal biogenesis, including the regulation of cell cycle progression, cell proliferation, migration and invasion. For example, RIOK1 promotes growth and metastasis of colorectal cancer cells in vitro and in vivo 10,30 . RIOK3 promotes growth, survival, migration and invasion of glioma cells 9 .…”

“…In recent years, studies on the involvements of RIO kinases in tumours have gradually increased. Knockdown of RIOK1 inhibits the proliferation, migration and invasion in breast, lung and colon cancer cells 10 . Stable overexpression of RIOK3 promotes proliferation, invasion and migration of glioma cells, while silencing of RIOK3 inhibits proliferation, migration and invasion, and induces apoptosis in glioma cells 9 .…”

A kinase-dependent checkpoint prevents escape of immature ribosomes into the translating pool

“…Rio1 is conserved throughout all domains of life. While Rio1 is critical for ribosome assembly and cell viability in yeast, it plays an equally important role during ribosome assembly in human cells (Weinberg et al, 2017). Intriguingly, whole genome sequencing of cancer samples reveals that diverse cancers accumulate mutations in Pno1 that are either directly adjacent to Pno1-KKKF, or similarly contact either the rRNA, Nob1, or ribosomal proteins (Figure S6, TCGA Research Network: https://www.cancer.gov/tcga).…”

“…Depletion of Rio1 or overexpression of a catalytically-inactive Rio1 mutant leads to the accumulation of 20S pre-rRNA and assembly factors in 80S-like ribosomes (Belhabich-Baumas et al, 2017;Ferreira-Cerca et al, 2014;Vanrobays et al, 2001;Widmann et al, 2012). However, the role Rio1 plays in 18S rRNA maturation and ribosome assembly remains unknown, despite its interest as a target for the development of anti-cancer drugs (Kiburu and LaRonde-LeBlanc, 2012;Kubinski et al, 2017;Mielecki et al, 2013;Read et al, 2013;Weinberg et al, 2017), and the observation that RIOK1 mutations accumulate in human cancers (TCGA Research Network:…”

Rational Discovery of Dual-Action Multi-Target Kinase Inhibitor for Precision Anti-Cancer Therapy Using Structural Systems Pharmacology

“…The anti-cancer activity of levosimendan mainly origins from the modulation of RNA processing pathway by the inhibition of atypical kinase RIOK1. RIOK1 represents a new anticancer drug target [46,47], and the chemical space of its inhibitors has just emerged. Tyrosine kinase inhibitors have been approved in the treatment of lymphoma [48,49].…”