Journal Article

DKFZ-2017-05635

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Glioma-induced inhibition of caspase-3 in microglia promotes a tumor-supportive phenotype.

Shen, X. ; Burguillos, M. A. ; Osman, A. M. ; Frijhoff, J. ; Carrillo-Jiménez, A. ; Kanatani, S. ; Augsten, M.DKFZ* ; Saidi, D. ; Rodhe, J. ; Kavanagh, E. ; Rongvaux, A. ; Rraklli, V. ; Nyman, U. ; Holmberg, J. ; Östman, A. ; Flavell, R. A. ; Barragan, A. ; Venero, J. L. ; Blomgren, K. ; Joseph, B.

2016
Nature America Inc. New York, NY

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Please use a persistent id in citations: doi:10.1038/ni.3545

Abstract: Glioma cells recruit and exploit microglia (the resident immune cells of the brain) for their proliferation and invasion ability. The underlying molecular mechanism used by glioma cells to transform microglia into a tumor-supporting phenotype has remained elusive. We found that glioma-induced microglia conversion was coupled to a reduction in the basal activity of microglial caspase-3 and increased S-nitrosylation of mitochondria-associated caspase-3 through inhibition of thioredoxin-2 activity, and that inhibition of caspase-3 regulated microglial tumor-supporting function. Furthermore, we identified the activity of nitric oxide synthase 2 (NOS2, also known as iNOS) originating from the glioma cells as a driving stimulus in the control of microglial caspase-3 activity. Repression of glioma NOS2 expression in vivo led to a reduction in both microglia recruitment and tumor expansion, whereas depletion of microglial caspase-3 gene promoted tumor growth. Our results provide evidence that inhibition of the denitrosylation of S-nitrosylated procaspase-3 mediated by the redox protein Trx2 is a part of the microglial pro-tumoral activation pathway initiated by glioma cancer cells.

Keyword(s): Mitochondrial Proteins ; TXN2 protein, human ; Thioredoxins ; Nitric Oxide Synthase Type II ; Caspase 3

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Contributing Institute(s):

1. Vaskuläre Onkologie und Metastasierung (A190)

Research Program(s):

1. 311 - Signalling pathways, cell and tumor biology (POF3-311) (POF3-311)

Appears in the scientific report 2016

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Database coverage:
; BIOSIS Previews ; Current Contents - Life Sciences ; Ebsco Academic Search ; IF >= 15 ; JCR ; NCBI Molecular Biology Database ; Nationallizenz ; SCOPUS ; Science Citation Index ; Science Citation Index Expanded ; Thomson Reuters Master Journal List ; Web of Science Core Collection

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