Glioma-induced inhibition of caspase-3 in microglia promotes a tumor-supportive phenotype.
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.
Department of Oncology-Pathology, Cancer Centrum Karolinska, Karolinska Institutet, Stockholm, Sweden.
Xianli
X
Shen
Department of Oncology-Pathology, Cancer Centrum Karolinska, Karolinska Institutet, Stockholm, Sweden.
Miguel A
MA
Burguillos
Department of Women's and Children's Health, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden.|Department of Pediatric Oncology, Karolinska University Hospital, Stockholm, Sweden.
Ahmed M
AM
Osman
Department of Oncology-Pathology, Cancer Centrum Karolinska, Karolinska Institutet, Stockholm, Sweden.
Jeroen
J
Frijhoff
Departamento de Bioquímica y Biología Molecular, Universidad de Sevilla, Sevilla, Spain.|Instituto de Biomedicina de Sevilla, Hospital Universitario Virgen del Rocío/CSIC/Universidad de Sevilla, Sevilla, Spain.
Alejandro
http://orcid.org/0000-0002-3023-4268
A
Carrillo-Jiménez
Center for Infectious Medicine, Department of Medicine, Karolinska Institutet, Stockholm, Sweden.|Department of Molecular Biosciences, the Wenner-Gren Institute, Stockholm University, Stockholm, Sweden.
Sachie
S
Kanatani
Department of Oncology-Pathology, Cancer Centrum Karolinska, Karolinska Institutet, Stockholm, Sweden.
Martin
M
Augsten
Department of Oncology-Pathology, Cancer Centrum Karolinska, Karolinska Institutet, Stockholm, Sweden.
Dalel
D
Saidi
Department of Oncology-Pathology, Cancer Centrum Karolinska, Karolinska Institutet, Stockholm, Sweden.
Johanna
http://orcid.org/0000-0002-6515-0080
J
Rodhe
Department of Oncology-Pathology, Cancer Centrum Karolinska, Karolinska Institutet, Stockholm, Sweden.
Edel
E
Kavanagh
Department of Immunobiology, Yale University School of Medicine, New Haven, Connecticut, USA.
Anthony
A
Rongvaux
Department of Cell and Molecular Biology, Ludwig Institute for Cancer Research, Karolinska Institutet, Stockholm, Sweden.
Vilma
V
Rraklli
Department of Cell and Molecular Biology, Ludwig Institute for Cancer Research, Karolinska Institutet, Stockholm, Sweden.
Ulrika
U
Nyman
Department of Cell and Molecular Biology, Ludwig Institute for Cancer Research, Karolinska Institutet, Stockholm, Sweden.
Johan
J
Holmberg
Department of Oncology-Pathology, Cancer Centrum Karolinska, Karolinska Institutet, Stockholm, Sweden.
Arne
A
Östman
Department of Immunobiology, Yale University School of Medicine, New Haven, Connecticut, USA.|Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, Connecticut, USA.
Richard A
RA
Flavell
Center for Infectious Medicine, Department of Medicine, Karolinska Institutet, Stockholm, Sweden.|Department of Molecular Biosciences, the Wenner-Gren Institute, Stockholm University, Stockholm, Sweden.
Antonio
A
Barragan
Departamento de Bioquímica y Biología Molecular, Universidad de Sevilla, Sevilla, Spain.|Instituto de Biomedicina de Sevilla, Hospital Universitario Virgen del Rocío/CSIC/Universidad de Sevilla, Sevilla, Spain.
Jose Luis
JL
Venero
Department of Women's and Children's Health, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden.|Department of Pediatric Oncology, Karolinska University Hospital, Stockholm, Sweden.
Klas
K
Blomgren
Department of Oncology-Pathology, Cancer Centrum Karolinska, Karolinska Institutet, Stockholm, Sweden.
Bertrand
B
Joseph
D000818:Animals; D053148:Caspase 3 / Q000378:metabolism*; D045744:Cell Line, Tumor; D002465:Cell Movement; D004195:Disease Models, Animal; D004789:Enzyme Activation; D055785:Gene Knockdown Techniques; D005910:Glioma / Q000276:immunology / Q000378:metabolism* / Q000473:pathology*; D064593:Heterografts; D006801:Humans; D008297:Male; D051379:Mice; D017628:Microglia / Q000276:immunology / Q000378:metabolism*; D008928:Mitochondria / Q000378:metabolism; D024101:Mitochondrial Proteins / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II / Q000235:genetics / Q000378:metabolism; D010641:Phenotype; D013879:Thioredoxins / Q000378:metabolism; D047368:Tumor Burden
D024101:Mitochondrial Proteins; C467002:TXN2 protein, human; D013879:Thioredoxins; D052247:Nitric Oxide Synthase Type II; D053148:Caspase 3