Dual Specificity Kinase DYRK3 Promotes Aggressiveness of Glioblastoma by Altering Mitochondrial Morphology and Function

• Published in: International journal of molecular sciences 2021-03, Vol.22 (6), p.2982
• Main Authors: Kim, Kyeongmin, Lee, Sungmin, Kang, Hyunkoo, Shin, Eunguk, Kim, Hae Yu, Youn, HyeSook, Youn, BuHyun
• Format: Article
• Language: English
• Subjects: Adaptor Proteins, Signal Transducing - genetics; AKT1 protein; Animals; Brain cancer; Brain tumors; Cell division; Cell Line, Tumor; Cell Proliferation - genetics; Cell Proliferation - radiation effects; Chemotherapy; Dynamin; Dynamins - genetics; DYRK3; Gene expression; Gene Expression Regulation, Neoplastic - radiation effects; Glioblastoma; Glioblastoma - genetics; Glioblastoma - pathology; Glioblastoma - radiotherapy; glioblastoma multiforme; Glycolysis; Humans; Kinases; Malignancy; Medical prognosis; Metabolic flux; Metabolism; Mice; Mitochondria; Mitochondria - genetics; Mitochondria - pathology; Mitochondria - radiation effects; mitochondrial fission; Morphology; Oxidative phosphorylation; Oxidative Phosphorylation - radiation effects; Patients; Phosphorylation; Proline; Protein-Serine-Threonine Kinases - genetics; Protein-Tyrosine Kinases - genetics; Proteins; Proto-Oncogene Proteins c-akt - genetics; Radiation effects; Radiation therapy; Radiation Tolerance - genetics; Radioresistance; Rapamycin; Respiration; TOR protein; Tumor cells; Tumors; Tyrosine; Xenograft Model Antitumor Assays; Xenografts; Xenotransplantation
• ISSN: 1422-0067; 1661-6596; 1422-0067
• DOI: 10.3390/ijms22062982

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.