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CCRK depletion inhibits glioblastoma cell proliferation in a cilium-dependent manner
Ying Yang1, Niina Roine, Tomi P Mäkelä
1Institute of Biotechnology, University of Helsinki, Helsinki 00790, Finland.
Abstract:
Loss of primary cilia is frequently observed in tumour cells, including glioblastoma cells, and proposed to benefit tumour growth, but a causal link has not been established. Here, we show that CCRK (cell cycle-related kinase) and its substrate ICK (intestinal cell kinase) inhibit ciliogenesis. Depletion of CCRK leads to accumulation of ICK at ciliary tips, altered ciliary transport and inhibition of cell cycle re-entry in NIH3T3 fibroblasts. In glioblastoma cells with deregulated high levels of CCRK, its depletion restores cilia through ICK and an ICK-related kinase MAK, thereby inhibiting glioblastoma cell proliferation. These results indicate that inhibition of ciliogenesis might be a mechanism used by cancer cells to provide a growth advantage.
Insights
Cancer cells, including glioblastoma, lose primary cilia to promote growth. This study reveals cell cycle-related kinase (CCRK) and intestinal cell kinase (ICK) inhibit cilia formation, suggesting a new cancer growth mechanism.
Area of Science:
- Oncology
- Cell Biology
- Molecular Biology
Background:
- Loss of primary cilia is common in tumors like glioblastoma, but its direct role in tumor growth is unproven.
- Primary cilia are crucial cellular antennae involved in signaling and cell cycle regulation.
Purpose of the Study:
- To investigate the causal link between primary cilia loss and tumor growth.
- To identify molecular mechanisms regulating ciliogenesis in cancer cells.
Main Methods:
- Utilized NIH3T3 fibroblasts and glioblastoma cell lines.
- Employed gene depletion techniques to study the roles of CCRK and ICK.
- Analyzed ciliary structure, protein localization, and cell proliferation.
Main Results:
- CCRK and ICK were identified as inhibitors of ciliogenesis.
- Depleting CCRK in fibroblasts led to ICK accumulation at ciliary tips and inhibited cell cycle re-entry.
- Reducing high CCRK levels in glioblastoma cells restored cilia via ICK and MAK, suppressing proliferation.
Conclusions:
- Inhibition of ciliogenesis by CCRK and ICK is a mechanism cancer cells use to gain a growth advantage.
- Restoring cilia formation can inhibit glioblastoma cell proliferation.
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