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
Ivi Antoniadou
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
Dorival Mendes Rodrigues-Junior
Department of Medical Biochemistry and Microbiology, Science for Life Laboratory, Uppsala University, Box 582, SE-751 23, Uppsala, Sweden
Odysseia Savvoulidou
Department of Cardiovascular and Renal Research, Institute of Molecular Medicine, University of Southern Denmark, J. B. Winslowsvej 21, 3, 5000, Odense C, Denmark
Laia Caja
Department of Medical Biochemistry and Microbiology, Science for Life Laboratory, Uppsala University, Box 582, SE-751 23, Uppsala, Sweden
Antonia Katsouda
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
Daniel F.J. Ketelhuth
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
Jane Stubbe
Department of Cardiovascular and Renal Research, Institute of Molecular Medicine, University of Southern Denmark, J. B. Winslowsvej 21, 3, 5000, Odense C, Denmark
Kirsten Madsen
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
Aristidis Moustakas
Department of Medical Biochemistry and Microbiology, Science for Life Laboratory, Uppsala University, Box 582, SE-751 23, Uppsala, Sweden; Corresponding author. Uppsala University, Department of Medical Biochemistry and Microbiology, Cancer; BMC Husargatan 3, 752 37, Uppsala, Sweden.
Andreas Papapetropoulos
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; Corresponding author. Laboratory of Pharmacology, Department of Pharmacy, National and Kapodistrian University of Athens, Athens, University Campus Zografou, 15771, Greece.
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 (H2S) producing enzymes and its expression contributes to tumorigenesis and angiogenesis but its role in glioblastoma development remains poorly understood. 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.
