The Atypical Kinase RIOK1 Promotes Tumor Growth and Invasive Behavior
Florian Weinberg1, Nadine Reischmann2, Lisa Fauth3
1Institute of Molecular Medicine and Cell Research (IMMZ), Faculty of Medicine, Albert-Ludwigs-University (ALU), Freiburg, Germany; Faculty of Biology, ALU, Freiburg, Germany; BIOSS Centre for Biological Signalling Studies, BIOSS, ALU, Germany.
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.
Insights
RIOK1 kinase is crucial for the proliferation and invasiveness of RAS-mutant cancers. Targeting RIOK1 may offer a new therapeutic strategy for these aggressive tumors.
Area of Science:
- Oncology
- Molecular Biology
- Cell Biology
Background:
- RIO kinases are atypical kinases implicated in various cellular processes but remain poorly understood in mammalian systems.
- Overexpression of RIO kinases is observed across diverse tumor types, suggesting a potential role in cancer development.
Purpose of the Study:
- To investigate the functional role of RIO kinases, specifically RIOK1, in different cancer cell types.
- To determine the specific context, such as RAS mutation status, in which RIOK1 influences cancer cell behavior.
- To explore the molecular mechanisms by which RIOK1 affects cancer progression and identify potential therapeutic targets.
Main Methods:
- Utilized isogenic cancer cell lines (colon, breast, lung) with varying RAS mutation status.
- Performed knockdown experiments for RIOK1, RIOK2, and RIOK3.
- Assessed proliferation and invasiveness in 2D and 3D culture systems.
- Investigated RIOK1's effect on NF-κB signaling and cell cycle progression.
- Employed proteomic analysis to identify RIOK1-regulated proteins.
- Evaluated RIOK1's role in lung colonization using in vivo models.
Main Results:
- RIOK1 knockdown significantly impaired proliferation and invasiveness in colon, breast, and lung cancer cells, particularly those with RAS mutations.
- RIOK1's effects were specific to RAS-mutant contexts, with no impact on RAS wildtype or Bcr-Abl-driven cells.
- RIOK1 was found to activate NF-κB signaling and promote cell cycle progression.
- Proteomic analysis identified Metadherin and Stathmin1 as RIOK1-regulated pro-invasive proteins.
- RIOK1 overexpression correlates with different subtypes of human lung and breast cancer and promotes lung colonization in vivo.
Conclusions:
- RIOK1 plays a critical role in the proliferation and invasiveness of RAS-driven cancers.
- RIOK1's activation of NF-κB signaling and regulation of key proteins contribute to cancer progression.
- RIOK1 is a potential therapeutic target, especially for cancers with activating RAS mutations.
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