Dual Specificity Kinase DYRK3 Promotes Aggressiveness of Glioblastoma by Altering Mitochondrial Morphology and
Kyeongmin Kim1, Sungmin Lee1, Hyunkoo Kang1
1Department of Integrated Biological Science, Pusan National University, Busan 46241, Korea.
Abstract:
Glioblastoma multiforme (GBM) is a malignant primary brain tumor with poor patient prognosis. Although the standard treatment of GBM is surgery followed by chemotherapy and radiotherapy, often a small portion of surviving tumor cells acquire therapeutic resistance and become more aggressive. Recently, altered kinase expression and activity have been shown to determine metabolic flux in tumor cells and metabolic reprogramming has emerged as a tumor progression regulatory mechanism. Here we investigated novel kinase-mediated metabolic alterations that lead to acquired GBM radioresistance and malignancy. We utilized transcriptomic analyses within a radioresistant GBM orthotopic xenograft mouse model that overexpresses the dual specificity tyrosine-phosphorylation-regulated kinase 3 (DYRK3). We find that within GBM cells, radiation exposure induces DYRK3 expression and DYRK3 regulates mammalian target of rapamycin complex 1 (mTORC1) activity through phosphorylation of proline-rich AKT1 substrate 1 (PRAS40). We also find that DYRK3 knockdown inhibits dynamin-related protein 1 (DRP1)-mediated mitochondrial fission, leading to increased oxidative phosphorylation (OXPHOS) and reduced glycolysis. Importantly, enforced DYRK3 downregulation following irradiation significantly impaired GBM cell migration and invasion. Collectively, we suggest DYRK3 suppression may be a novel strategy for preventing GBM malignancy through regulating mitochondrial metabolism.
Insights
Dual specificity tyrosine-phosphorylation-regulated kinase 3 (DYRK3) promotes glioblastoma radioresistance and malignancy. Suppressing DYRK3 inhibits tumor cell migration and invasion by altering mitochondrial metabolism.
Area of Science:
- Oncology
- Molecular Biology
- Metabolism
Background:
- Glioblastoma multiforme (GBM) is an aggressive brain tumor with poor prognosis.
- Standard GBM treatment often leads to therapeutic resistance and increased malignancy.
- Metabolic reprogramming, driven by kinase activity, is a key mechanism in tumor progression.
Purpose of the Study:
- Investigate novel kinase-mediated metabolic alterations contributing to acquired GBM radioresistance and malignancy.
- Identify the role of dual specificity tyrosine-phosphorylation-regulated kinase 3 (DYRK3) in GBM radioresistance.
Main Methods:
- Utilized transcriptomic analyses in a radioresistant GBM orthotopic xenograft mouse model.
- Examined DYRK3 expression and its downstream effects on mTORC1, PRAS40, DRP1, and mitochondrial metabolism.
- Assessed the impact of DYRK3 knockdown on GBM cell migration and invasion post-irradiation.
Main Results:
- Radiation exposure induces DYRK3 expression in GBM cells.
- DYRK3 regulates mammalian target of rapamycin complex 1 (mTORC1) activity via PRAS40 phosphorylation.
- DYRK3 knockdown inhibits DRP1-mediated mitochondrial fission, increasing oxidative phosphorylation (OXPHOS) and reducing glycolysis.
- Enforced DYRK3 downregulation impairs GBM cell migration and invasion.
Conclusions:
- DYRK3 plays a critical role in acquired GBM radioresistance and malignancy.
- DYRK3 regulates mitochondrial metabolism and cell invasion through pathways involving mTORC1 and DRP1.
- DYRK3 suppression represents a potential therapeutic strategy to combat GBM progression and enhance treatment efficacy.
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