Department of Oncology-Pathology, Cancer Centrum Karolinska, Karolinska Institutet, Stockholm, Sweden.
Department of Women's and Children's Health, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden.
Nat Immunol. 2016 Nov;17(11):1282-1290. doi: 10.1038/ni.3545. Epub 2016 Sep 12.
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.
神经胶质瘤细胞招募并利用小胶质细胞（大脑的常驻免疫细胞）来促进其增殖和侵袭能力。然而，神经胶质瘤细胞将小胶质细胞转化为支持肿瘤生长的表型的潜在分子机制仍未被阐明。我们发现，神经胶质瘤诱导的小胶质细胞转化与小胶质细胞半胱氨酸蛋白酶-3的基础活性降低以及线粒体相关半胱氨酸蛋白酶-3的 S-亚硝基化增加有关，这是通过抑制硫氧还蛋白-2的活性而实现的，并且抑制半胱氨酸蛋白酶-3调节小胶质细胞的肿瘤支持功能。此外，我们确定了来自神经胶质瘤细胞的一氧化氮合酶 2（NOS2，也称为 iNOS）的活性是控制小胶质细胞半胱氨酸蛋白酶-3活性的驱动刺激因素。体内抑制神经胶质瘤 NOS2 的表达会导致小胶质细胞募集和肿瘤扩张减少，而耗尽小胶质细胞半胱氨酸蛋白酶-3 基因则会促进肿瘤生长。我们的结果提供了证据，表明由氧化还原蛋白 Trx2 介导的 S-亚硝基化的 procaspase-3 的去亚硝基化抑制是由神经胶质瘤癌细胞引发的小胶质细胞促肿瘤激活途径的一部分。
