Cystathionine gamma-lyase (CTH) inhibition attenuates glioblastoma formation

Maria Peleli, Ivi Antoniadou, Dorival Mendes Rodrigues-Junior, Odysseia Savvoulidou, Laia Caja, Antonia Katsouda, Daniel F.J. Ketelhuth, Jane Stubbe, Kirsten Madsen, Aristidis Moustakas, Andreas Papapetropoulos

Research output: Contribution to journalArticlepeer-review

4 Scopus citations

Abstract

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.

Original languageEnglish (US)
Article number102773
JournalRedox Biology
Volume64
DOIs
StatePublished - Aug 2023
Externally publishedYes

Keywords

  • Brain blood vessels
  • Cystathionine gamma-lyase (CTH)
  • Glioblastoma stem cells (GSC)
  • Sex determining region Y-Box 2 (SOX2)

ASJC Scopus subject areas

  • Organic Chemistry

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