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

• DOI: 10.1038/ni.3545
• Publication Date: 2016-09-12T17:24:10Z
• Authors: Xianli Shen; Miguel A Burguillos; Ahmed M Osman; Jeroen Frijhoff; Alejandro Carrill...; Sachie Kanatani; Martin Augsten; Dalel Saidi; Johanna Rodhe; Edel Kavanagh; Anthony Rongvaux; Vilma Rraklli; Ulrika Nyman; Johan Holmberg; Arne Östman; Richard A Flavell; Antonio Barragan; Jose Luis Venero; Klas Blomgren; Bertrand Joseph
• Keywords: Male; Caspase 3; Nitric Oxide Synthase Type II; Glioma; Mitochondria; Tumor Burden; 3. Good health; Enzyme Activation; Mitochondrial Proteins; Disease Models, Animal; Mice; Phenotype; Thioredoxins; Cell Movement; Cell Line, Tumor; Gene Knockdown Techniques; Animals; Heterografts; Humans; cancer; Microglia; innate immune cells

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 $\textit{in vivo}$ 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.