Cystathionine gamma-lyase (CTH) inhibition attenuates glioblastoma formation.
| Autor: | Peleli M; Department of Medical Biochemistry and Microbiology, Science for Life Laboratory, Uppsala University, Box 582, SE-751 23, Uppsala, Sweden; Clinical, Experimental Surgery and Translational Research Center, Biomedical Research Foundation of the Academy of Athens, Athens, Greece; Department of Cardiovascular and Renal Research, Institute of Molecular Medicine, University of Southern Denmark, J. B. Winslowsvej 21, 3, 5000, Odense C, Denmark., Antoniadou I; Clinical, Experimental Surgery and Translational Research Center, Biomedical Research Foundation of the Academy of Athens, Athens, Greece; Laboratory of Pharmacology, Department of Pharmacy, National and Kapodistrian University of Athens, Athens, Greece., Rodrigues-Junior DM; Department of Medical Biochemistry and Microbiology, Science for Life Laboratory, Uppsala University, Box 582, SE-751 23, Uppsala, Sweden., Savvoulidou O; Department of Cardiovascular and Renal Research, Institute of Molecular Medicine, University of Southern Denmark, J. B. Winslowsvej 21, 3, 5000, Odense C, Denmark., Caja L; Department of Medical Biochemistry and Microbiology, Science for Life Laboratory, Uppsala University, Box 582, SE-751 23, Uppsala, Sweden., Katsouda A; Clinical, Experimental Surgery and Translational Research Center, Biomedical Research Foundation of the Academy of Athens, Athens, Greece; Laboratory of Pharmacology, Department of Pharmacy, National and Kapodistrian University of Athens, Athens, Greece., Ketelhuth DFJ; Department of Cardiovascular and Renal Research, Institute of Molecular Medicine, University of Southern Denmark, J. B. Winslowsvej 21, 3, 5000, Odense C, Denmark; Division of Cardiovascular Medicine, Center for Molecular Medicine, Department of Medicine, Karolinska Institute, Karolinska University Hospital, Stockholm, Sweden., Stubbe J; Department of Cardiovascular and Renal Research, Institute of Molecular Medicine, University of Southern Denmark, J. B. Winslowsvej 21, 3, 5000, Odense C, Denmark., Madsen K; Department of Cardiovascular and Renal Research, Institute of Molecular Medicine, University of Southern Denmark, J. B. Winslowsvej 21, 3, 5000, Odense C, Denmark; Department of Pathology, Odense University Hospital, J.B Winslowsvej 15, 5000, Odense C, Denmark., Moustakas A; Department of Medical Biochemistry and Microbiology, Science for Life Laboratory, Uppsala University, Box 582, SE-751 23, Uppsala, Sweden. Electronic address: aris.moustakas@imbim.uu.se., Papapetropoulos A; Clinical, Experimental Surgery and Translational Research Center, Biomedical Research Foundation of the Academy of Athens, Athens, Greece; Laboratory of Pharmacology, Department of Pharmacy, National and Kapodistrian University of Athens, Athens, Greece. Electronic address: apapapet@pharm.uoa.gr. |
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| Jazyk: | angličtina |
| Zdroj: | Redox biology [Redox Biol] 2023 Aug; Vol. 64, pp. 102773. Date of Electronic Publication: 2023 Jun 05. |
| DOI: | 10.1016/j.redox.2023.102773 |
| Abstrakt: | Purpose: Glioblastoma (GBM) is the most common type of adult brain tumor with extremely poor survival. Cystathionine-gamma lyase (CTH) is one of the main Hydrogen Sulfide (H Methods: and Principal Results: An established allogenic immunocompetent in vivo GBM model was used in C57BL/6J WT and CTH KO mice where the tumor volume and tumor microvessel density were blindly measured by stereological analysis. Tumor macrophage and stemness markers were measured by blinded immunohistochemistry. Mouse and human GBM cell lines were used for cell-based analyses. In human gliomas, the CTH expression was analyzed by bioinformatic analysis on different databases. In vivo, the genetic ablation of CTH in the host led to a significant reduction of the tumor volume and the protumorigenic and stemness transcription factor sex determining region Y-box 2 (SOX2). The tumor microvessel density (indicative of angiogenesis) and the expression levels of peritumoral macrophages showed no significant changes between the two genotypes. Bioinformatic analysis in human glioma tumors revealed that higher CTH expression is positively correlated to SOX2 expression and associated with worse overall survival in all grades of gliomas. Patients not responding to temozolomide have also higher CTH expression. In mouse or human GBM cells, pharmacological inhibition (PAG) or CTH knockdown (siRNA) attenuates GBM cell proliferation, migration and stem cell formation frequency. Major Conclusions: Inhibition of CTH could be a new promising target against glioblastoma formation. Competing Interests: Declaration of competing interest The authors declare no conflict of interest. (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.) |
| Databáze: | MEDLINE |
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