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

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.

DYRK1B-STAT3 Drives Cardiac Hypertrophy and Heart Failure by Impairing Mitochondrial Bioenergetics

“…14 DYRK3 has recently been found to reduce mitochondrial oxidative phosphorylation and increase glycolysis by activating Drp-1 (dynamic-related protein 1)–mediated mitochondrial fission. 15 In this study, we found that the transcriptional level of DYRK1B, rather than other members of the DYRK family, was distinctively upregulated in myocardium of patients who had dilated cardiopathy (DCM), ischemic cardiomyopathy, and hypertrophic cardiomyopathy (HCM) compared with those of patients with nonfailing myocardium, suggesting the indispensable role of DYRK1B in the progression of HF. In addition, it was recently reported that DYRK1B mutation is directly linked with human genetic diseases, its gain-of-function mutation at position 102 precisely predicts early-onset coronary artery disease, central obesity, hypertension, and diabetes, highlighting the important role of DYRK1B in energy metabolism and heart diseases.…”

Dual-Specificity, Tyrosine Phosphorylation-Regulated Kinases (DYRKs) and cdc2-Like Kinases (CLKs) in Human Disease, an Overview

“…DYRK3 promotes hepatocellular carcinoma [ 121 ] and glioblastoma [ 122 ]. DYRK3 is required for influenza virus replication [ 123 ].…”

“…DYRK2 is involved in various ways in cancer development (reviews: [119,120]). DYRK3 promotes hepatocellular carcinoma [121] and glioblastoma [122]. DYRK3 is required for influenza virus replication [123].…”

NRBF2-mediated autophagy contributes to metabolite replenishment and radioresistance in glioblastoma

“…The effects of NRBF2 knockdown and irradiation on cell invasion and migration capacity were investigated by transwell cell invasion/migration assays, as previously described 25 . Cells (2 × 10 5 in serum-free medium containing 1 mM glucose) were seeded into the upper chambers of a 24-well Transwell chamber (Corning, Corning, NY, USA) fitted with a 5 μm pore-size insert and treated with NRBF2 siRNA and/or radiation for 24 h. Next, the medium in the lower chamber was changed to medium containing 10% FBS.…”