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

doi:10.1016/j.redox.2023.102773

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^*

^*Kontaktforfatter

Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › peer review

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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.

Originalsprog	Engelsk
Artikelnummer	102773
Tidsskrift	Redox Biology
Vol/bind	64
Sider (fra-til)	102773
Antal sider	12
ISSN	2213-2317
DOI	https://doi.org/10.1016/j.redox.2023.102773 https://doi.org/10.1016/j.redox.2023.102773
Status	Udgivet - aug. 2023

Bibliografisk note

Funding Information:
This work was funded by the Swedish Research Council International Postdoc Grant (Vetenskapsrådet, Grant number: 2019-00534 ) to M.P and the Swedish Cancer Society ( CAN2018/469 , CAN2021/1506Pj01H ) to A.M. D.F.J.K is supported by grants from the Novo Nordisk Foundation (MeRIAD consortium, 0064142 ), and the University of Southern Denmark .

Publisher Copyright:
© 2023 The Authors

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Peleli, M., Antoniadou, I., Rodrigues-Junior, D. M., Savvoulidou, O., Caja, L., Katsouda, A., Ketelhuth, D. F. J., Stubbe, J., Madsen, K., Moustakas, A., & Papapetropoulos, A. (2023). Cystathionine gamma-lyase (CTH) inhibition attenuates glioblastoma formation. Redox Biology, 64, 102773. Artikel 102773. https://doi.org/10.1016/j.redox.2023.102773, https://doi.org/10.1016/j.redox.2023.102773

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title = "Cystathionine gamma-lyase (CTH) inhibition attenuates glioblastoma formation",

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.",

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

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

note = "Publisher Copyright: {\textcopyright} 2023 The Authors",

year = "2023",

month = aug,

doi = "10.1016/j.redox.2023.102773",

language = "English",

volume = "64",

pages = "102773",

journal = "Redox Biology",

issn = "2213-2317",

publisher = "Elsevier",

}

Peleli, M, Antoniadou, I, Rodrigues-Junior, DM, Savvoulidou, O, Caja, L, Katsouda, A, Ketelhuth, DFJ , Stubbe, J , Madsen, K, Moustakas, A & Papapetropoulos, A 2023, 'Cystathionine gamma-lyase (CTH) inhibition attenuates glioblastoma formation', Redox Biology, bind 64, 102773, s. 102773. https://doi.org/10.1016/j.redox.2023.102773, https://doi.org/10.1016/j.redox.2023.102773

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

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)

U2 - 10.1016/j.redox.2023.102773

DO - 10.1016/j.redox.2023.102773

M3 - Journal article

C2 - 37300955

AN - SCOPUS:85161010651

SN - 2213-2317

VL - 64

SP - 102773

JO - Redox Biology

JF - Redox Biology

M1 - 102773

ER -

Cystathionine gamma-lyase (CTH) inhibition attenuates glioblastoma formation

Abstract

Bibliografisk note

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