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Nat Immunol. 2016 Nov;17(11):1282-1290. doi: 10.1038/ni.3545. Epub 2016 Sep 12.

Glioma-induced inhibition of caspase-3 in microglia promotes a tumor-supportive phenotype.

Author information

1
Department of Oncology-Pathology, Cancer Centrum Karolinska, Karolinska Institutet, Stockholm, Sweden.
2
Department of Women's and Children's Health, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden.
3
Department of Pediatric Oncology, Karolinska University Hospital, Stockholm, Sweden.
4
Departamento de Bioquímica y Biología Molecular, Universidad de Sevilla, Sevilla, Spain.
5
Instituto de Biomedicina de Sevilla, Hospital Universitario Virgen del Rocío/CSIC/Universidad de Sevilla, Sevilla, Spain.
6
Center for Infectious Medicine, Department of Medicine, Karolinska Institutet, Stockholm, Sweden.
7
Department of Molecular Biosciences, the Wenner-Gren Institute, Stockholm University, Stockholm, Sweden.
8
Department of Immunobiology, Yale University School of Medicine, New Haven, Connecticut, USA.
9
Department of Cell and Molecular Biology, Ludwig Institute for Cancer Research, Karolinska Institutet, Stockholm, Sweden.
10
Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, Connecticut, USA.

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.

PMID:
27618552
DOI:
10.1038/ni.3545
[Indexed for MEDLINE]

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