Cancer Research Institute, Southern Medical University, Guangzhou, 510515, China; Guangdong Provincial Key Laboratory of Cancer Immunotherapy Research, Guangzhou, 510515, China; Guangzhou Key Laboratory of Tumor Immunology Research, Southern Medical University, Guangzhou, 510515, China.
Cancer Research Institute, Southern Medical University, Guangzhou, 510515, China.
Biochem Biophys Res Commun. 2019 Aug 6;515(4):517-523. doi: 10.1016/j.bbrc.2019.05.114. Epub 2019 May 29.
Previous studies have suggested that nitric oxide (NO) which is synthetized by nitric oxide synthase (NOS) is closely related to the carcinogenesis and progression of colon cancer. However, the precise physiopathological role of NO on colon cancer remains unclear, and a lot of related studies focused on NOS2 and NOS3, but little on NOS1. Here, stable overexpression NOS1 of colon cancer cells were constructed to investigate whether NOS1 plays a special role in colon cancer. We observed that NOS1 protein was presented in mitochondria. Both the basal and cisplatin-induced mitochondrial superoxide were inhibited by NOS1, and the cisplatin-induced apoptosis was also inhibited by NOS1. Geldanamycin, a Hsp90 N-terminal inhibitor, was able to impede NOS1 translocation into mitochondria and reverse NOS1-induced apoptosis resistance. Importantly, SIRT3 activity was enhanced by NOS1, which contributes to the low level of mitochondrial superoxide and apoptosis resistance. Our data suggest a link between NOS1 and apoptosis resistance in colon cancer cells through mtNOS1-SIRT3-SOD2 axis. Furthermore, NOS1-induced apoptosis resistance could be reversed by inhibiting mitochondrial translocation of NOS1.
先前的研究表明，一氧化氮合酶（NOS）合成的一氧化氮（NO）与结肠癌的发生和发展密切相关。然而，NO 对结肠癌的确切生理病理作用尚不清楚，许多相关研究集中在 NOS2 和 NOS3 上，而对 NOS1 的研究较少。在这里，构建了稳定过表达结肠癌细胞 NOS1 的模型，以研究 NOS1 是否在结肠癌中发挥特殊作用。我们观察到 NOS1 蛋白存在于线粒体中。NOS1 抑制基础状态和顺铂诱导的线粒体超氧阴离子产生，同时抑制顺铂诱导的细胞凋亡。Hsp90N 端抑制剂格尔德霉素（geldanamycin）能够阻止 NOS1 向线粒体的易位，并逆转 NOS1 诱导的凋亡抵抗。重要的是，NOS1 增强了 SIRT3 活性，这有助于降低线粒体中超氧阴离子的水平和凋亡抵抗。我们的数据表明，NOS1 通过 mtNOS1-SIRT3-SOD2 轴与结肠癌细胞中的凋亡抵抗之间存在联系。此外，通过抑制 NOS1 的线粒体易位可以逆转 NOS1 诱导的凋亡抵抗。
