TY - JOUR
T1 - Cystathionine gamma-lyase (CTH) inhibition attenuates glioblastoma formation
AU - Peleli, Maria
AU - Antoniadou, Ivi
AU - Rodrigues-Junior, Dorival Mendes
AU - Savvoulidou, Odysseia
AU - Caja, Laia
AU - Katsouda, Antonia
AU - Ketelhuth, Daniel F.J.
AU - Stubbe, Jane
AU - Madsen, Kirsten
AU - Moustakas, Aristidis
AU - Papapetropoulos, Andreas
N1 - Publisher Copyright:
© 2023 The Authors
PY - 2023/8
Y1 - 2023/8
N2 - 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.
AB - 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.
KW - Brain blood vessels
KW - Cystathionine gamma-lyase (CTH)
KW - Glioblastoma stem cells (GSC)
KW - Sex determining region Y-Box 2 (SOX2)
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U2 - 10.1016/j.redox.2023.102773
DO - 10.1016/j.redox.2023.102773
M3 - Article
C2 - 37300955
AN - SCOPUS:85161010651
SN - 2213-2317
VL - 64
JO - Redox Biology
JF - Redox Biology
M1 - 102773
ER -