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DYRK1A activates NFATC1 to increase glioblastoma migration.

ABSTRACT: Glioblastoma (GBM) is the most aggressive glioma, and is prone to develop resistance to chemotherapy and radiotherapy; hence, patients with glioblastoma have a high recurrence rate and a low 1-year survival rate. In addition, the pathogenesis of glioblastoma is complex and largely unknown, and the available treatments are limited. Here, we uncovered a fundamental role of DYRK1A in regulating NFATC1 in GBMs. We found that DYRK1A was highly expressed in glioma and glioblastoma cells, and its expression was positively correlated with that of NFATC1. Moreover, inhibition of DYRK1A promoted NFATC1 degradation in GBM cells and sharply reduced the transactivation of NFATC1, not only by decreasing the expression of NFATC1-targeted genes, but also by reducing the luciferase activity, and vice versa. However, DYRK1A had the opposite effect on NFATC2. Most importantly, our data suggest that DYRK1A inhibition reduces glioblastoma migration. Polypeptides derived from the DYRK1A-targeted motif of NFATC1, by competitively blocking DYRK1A kinase activity on NFATC1, clearly destabilized NFATC1 protein and impaired glioblastoma migration. We propose that the recovery of NFATC1 stability is a key oncogenic event in a large proportion of gliomas, and pharmacological inhibition of DYRK1A by polypeptides could represent a promising therapeutic intervention for GBM.

SUBMITTER: Liu H

PROVIDER: S-EPMC8446559 | biostudies-literature |

REPOSITORIES: biostudies-literature

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NFATc1 phosphorylation by DYRK1A increases its protein stability.

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Negative feedback Inhibition of NFATc1 by DYRK1A regulates bone homeostasis.

Project description:DYRK1A is a serine/threonine kinase that has been linked to mental retardation associated with Down syndrome. In the present report, we describe a previously unknown role for DYRK1A in bone homeostasis. The protein expression of DYRK1A increased during osteoclast differentiation. In vitro studies in osteoclasts revealed that DYRK1A inhibited osteoclastogenesis. Whereas DYRK1A phosphorylated and inhibited the osteoclastogenic transcription factor NFATc1, forced expression of NFATc1 induced DYRK1A expression, suggesting a negative feedback loop. Transgenic mice overexpressing DYRK1A by the extent of the increased gene dosage in Down syndrome exhibited significantly reduced bone mass despite the decreased osteoclastogenesis, which is reminiscent of osteoporotic bone phenotype in Down syndrome patients. In these mice, attenuated osteoblast differentiation and function in the presence of extra DYRK1A overrode the effect of impaired osteoclastogenesis. However, impeded osteoclastogenesis in DYRK1A transgenic mice was proven to be beneficial in protecting bone loss induced by inflammation or estrogen deficiency. These results provide novel insight into the role for DYRK1A in bone homeostasis as well as in bone destructive diseases, in which modulation of DYRK1A might be used as a strategy to treat unregulated bone resorption.

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Project description:Temozolomide (TMZ)-resistance hampers the therapeutic efficacy of this drug for glioblastoma (GBM) treatment in clinic, and emerging evidences suggested that exosomes from GBM-derived stem cells (GSCs) contributed to this process, but the detailed mechanisms are still largely unknown. In the present study, we reported that GSCs derived programmed death-ligand 1 (PD-L1) containing exosomes activated AMPK/ULK1 pathway mediated protective autophagy enhanced TMZ-resistance in GBM in vitro and in vivo. Specifically, we noticed that continuous low-dose TMZ stimulation promoted GSCs generation and PD-L1 containing exosomes (PD-L1-ex) secretion in GBM cells, and that PD-L1-ex inhibited cell apoptosis and promoted cell autophagy to increased TMZ-resistance in GBM cells, which were reversed by co-treating cells with the autophagy inhibitor 3-methyladenine (3-MA). Consistently, upregulation of PD-L1 also increased TMZ-resistance in TS-GBM cells, and silencing of PD-L1 sensitized TR-GBM cells to TMZ. In addition, PD-L1-ex activated AMPK/ULK1 pathway to induce autophagy in TMZ treated GBM cells, and the inhibitors for AMPK (compound C) and ULK1 (SBI-0206965) promoted cell apoptosis in GBM cells co-treated with PD-L1-ex and high-dose TMZ. Finally, we evidenced that PD-L1-ex promoted tumor growth and Ki67 protein expressions to increase TMZ-resistance in GBM in vivo. Collectively, we concluded that GSCs-derived PD-L1-ex activated AMPK1/ULK1 signaling cascade mediated autophagy to increase TMZ-resistance in GBM, and this study provided potential strategies to improve the therapeutic efficacy of TMZ in GBM.

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Project description:Glioblastomas (GBMs) are very aggressive tumors that are resistant to conventional chemo- and radiotherapy. New molecular therapeutic strategies are required to effectively eliminate the subpopulation of GBM tumor-initiating cells that are responsible for relapse. Since EGFR is altered in 50% of GBMs, it represents one of the most promising targets; however, EGFR kinase inhibitors have produced poor results in clinical assays, with no clear explanation for the observed resistance. We uncovered a fundamental role for the dual-specificity tyrosine phosphorylation-regulated kinase, DYRK1A, in regulating EGFR in GBMs. We found that DYRK1A was highly expressed in these tumors and that its expression was correlated with that of EGFR. Moreover, DYRK1A inhibition promoted EGFR degradation in primary GBM cell lines and neural progenitor cells, sharply reducing the self-renewal capacity of normal and tumorigenic cells. Most importantly, our data suggest that a subset of GBMs depends on high surface EGFR levels, as DYRK1A inhibition compromised their survival and produced a profound decrease in tumor burden. We propose that the recovery of EGFR stability is a key oncogenic event in a large proportion of gliomas and that pharmacological inhibition of DYRK1A could represent a promising therapeutic intervention for EGFR-dependent GBMs.

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DYRK1A-mediated PLK2 phosphorylation regulates the proliferation and invasion of glioblastoma cells.

Project description:Polo-like kinases (PLKs) are a family of serine-threonine kinases that exert regulatory effects on diverse cellular processes. Dysregulation of PLKs has been implicated in multiple cancers, including glioblastoma (GBM). Notably, PLK2 expression in GBM tumor tissue is lower than that in normal brains. Notably, high PLK2 expression is significantly correlated with poor prognosis. Thus, it can be inferred that PLK2 expression alone may not be sufficient for accurate prognosis evaluation, and there are unknown mechanisms underlying PLK2 regulation. In the present study, it was demonstrated that dual specificity tyrosine-phosphorylation-regulated kinase 1A (DYRK1A) interacts with and phosphorylates PLK2 at Ser358. DYRK1A-mediated phosphorylation of PLK2 increases its protein stability. Moreover, PLK2 kinase activity was markedly induced by DYRK1A, which was exemplified by the upregulation of alpha-synuclein S129 phosphorylation. Furthermore, it was found that phosphorylation of PLK2 by DYRK1A contributes to the proliferation, migration and invasion of GBM cells. DYRK1A further enhances the inhibition of the malignancy of GBM cells already induced by PLK2. The findings of the present study indicate that PLK2 may play a crucial role in GBM pathogenesis partially in a DYRK1A-dependent manner, suggesting that PLK2 Ser358 may serve as a therapeutic target for GBM.

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Global Phosphoproteomics of DYRK1A Inhibition in Glioblastoma Cells

Project description:Here we performed a detailed investigation to delineate the role of DYRK1A in glioblastoma, using both pharmacological and genetic tools combined with global phosphoproteomics. Our data show that DYRK1A inhibitors affect a much broader proportion of the phosphoproteome than DYRK1A knockdown. By overlaying these datasets we identify a pool of 61 putative novel DYRK1A targets, and validate CDC23 Ser588 as a bona-fide DYRK1A substrate. CDC23 is a ubiquitin ligase that degrades mitotic proteins, and DYRK1A inhibiton thereby leads to the accumulation of cyclin B and activation of CDK1.

2021-04-22 | PXD020441 | Pride

Epidermal growth factor-induced enhancement of glioblastoma cell migration in 3D arises from an intrinsic increase in speed but an extrinsic matrix- and proteolysis-dependent increase in persistence.

Project description:Epidermal growth factor (EGF) receptor-mediated cell migration plays a vital role in invasion of many tumor types. EGF receptor ligands increase invasiveness in vivo, but it remains unclear how consequent effects on intrinsic cell motility behavior versus effects on extrinsic matrix properties integrate to result in net increase of translational speed and/or directional persistence of migration in a 3D environment. Understanding this convolution is important for therapeutic targeting of tumor invasion, as key regulatory pathways for intrinsic versus extrinsic effects may not be coincident. Accordingly, we have undertaken a quantitative single-cell imaging study of glioblastoma cell movement in 3D matrices and on 2D substrata across a range of collagen densities with systematic variation of protease-mediated matrix degradation. In 3D, EGF induced a mild increase in cell speed and a strong increase in directional persistence, the latter depending heavily on matrix density and EGF-stimulated protease activity. In contrast, in 2D, EGF induced a similarly mild increase in speed but conversely a decrease in directional persistence (both independent of protease activity). Thus, the EGF-enhanced 3D tumor cell migration results only partially from cell-intrinsic effects, with override of cell-intrinsic persistence decrease by protease-mediated cell-extrinsic reduction of matrix steric hindrance.

| S-EPMC2555959 | biostudies-literature

Down-Regulation of Nfatc1 Suppresses Proliferation, Migration, Invasion, and Warburg Effect in Prostate Cancer Cells.

Project description:BACKGROUND Prostate cancer (PCa), accounting for 28% of all male cancer cases, is the second leading cause of cancer-related death among men. NFATc1, belonging to the NFAT family, is overexpressed in PCa and is correlated with the risk of recurrence after radical prostatectomy. MATERIAL AND METHODS In the present study, the expression of NFATc, c-myc, and PKM2 in PCa cells was regulated by lentiviruses and then detected by real-time PCR and Western blot analysis. Further, proliferation, invasion, and migration assays were performed. The glucose consumption and lactate production were assessed by biochemical detection. RESULTS We found that NFATc1 down-regulation significantly suppressed the proliferation and Warburg effect of PCa cells, concurrent with a decrease of c-myc and PKM2 expression. Likewise, the abilities of migration and invasion were also inhibited in NFATc1-silenced PCa cells. In addition, NFATc1 down-regulation-induced inhibition of cell proliferation, migration, invasion, and Warburg effect were counteracted by up-regulation of c-myc or PKM2. The expression of PKM2 was positively regulated by NFATc1 and c-myc expression. CONCLUSIONS These results indicate that NFATc1 down-regulation can suppress the proliferation, Warburg effect, and migration and invasion abilities of PCa cells, probably by regulating c-myc and PKM2 expression. NFATc1 may be a potential therapeutic target for PCa and could be used as a diagnosis or prognosis indicator of PCa.

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EGFR Activates a TAZ-Driven Oncogenic Program in Glioblastoma.

Project description:Hyperactivated EGFR signaling is a driver of various human cancers, including glioblastoma (GBM). Effective EGFR-targeted therapies rely on knowledge of key signaling hubs that transfer and amplify EGFR signaling. Here we focus on the transcription factor TAZ, a potential signaling hub in the EGFR signaling network. TAZ expression was positively associated with EGFR expression in clinical GBM specimens. In patient-derived GBM neurospheres, EGF induced TAZ through EGFR-ERK and EGFR-STAT3 signaling, and the constitutively active EGFRvIII mutation caused EGF-independent hyperactivation of TAZ. Genome-wide analysis showed that the EGFR-TAZ axis activates multiple oncogenic signaling mechanisms, including an EGFR-TAZ-RTK positive feedback loop, as well as upregulating HIF1α and other oncogenic genes. TAZ hyperactivation in GBM stem-like cells induced exogenous mitogen-independent growth and promoted GBM invasion, radioresistance, and tumorigenicity. Screening a panel of brain-penetrating EGFR inhibitors identified osimertinib as the most potent inhibitor of the EGFR-TAZ signaling axis. Systemic osimertinib treatment inhibited the EGFR-TAZ axis and in vivo growth of GBM stem-like cell xenografts. Overall these results show that the therapeutic efficacy of osimertinib relies on effective TAZ inhibition, thus identifying TAZ as a potential biomarker of osimertinib sensitivity. SIGNIFICANCE: This study establishes a genome-wide map of EGFR-TAZ signaling in glioblastoma and finds osimertinib effectively inhibits this signaling, justifying its future clinical evaluation to treat glioblastoma and other cancers with EGFR/TAZ hyperactivation. GRAPHICAL ABSTRACT: http://cancerres.aacrjournals.org/content/canres/81/13/3580/F1.large.jpg.

| S-EPMC8277712 | biostudies-literature

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