Bioactive Products and Metabolic Syndrome Group - BIOPROMET, Madrid Institute for Advanced Studies - IMDEA Food, CEI UAM+CSIC, Madrid, Spain.
GENYAL Nutrigenomic Platform, Madrid Institute for Advanced Studies - IMDEA Food, CEI UAM+CSIC, Madrid, Spain.
EMBO Rep. 2018 Sep;19(9). doi: 10.15252/embr.201643879. Epub 2018 Jul 18.
The NAD-dependent deacetylase SIRT1 can be oncogenic or tumor suppressive depending on the tissue. Little is known about the role of SIRT1 in non-small cell lung carcinoma (NSCLC), one of the deadliest cancers, that is frequently associated with mutated K-RAS Therefore, we investigated the effect of SIRT1 on K-RAS-driven lung carcinogenesis. We report that SIRT1 protein levels are downregulated by oncogenic K-RAS in a MEK and PI3K-dependent manner in mouse embryo fibroblasts (MEFs), and in human lung adenocarcinoma cell lines. Furthermore, Sirt1 overexpression in mice delays the appearance of K-Ras-driven lung adenocarcinomas, reducing the number and size of carcinomas at the time of death and extending survival. Consistently, lower levels of SIRT1 are associated with worse prognosis in human NSCLCs. Mechanistically, analysis of mouse Sirt1-Tg pneumocytes, isolated shortly after K-Ras activation, reveals that Sirt1 overexpression alters pathways involved in tumor development: proliferation, apoptosis, or extracellular matrix organization. Our work demonstrates a tumor suppressive role of SIRT1 in the development of K-RAS-driven lung adenocarcinomas in mice and humans, suggesting that the SIRT1-K-RAS axis could be a therapeutic target for NSCLCs.
NAD 依赖的去乙酰化酶 SIRT1 的作用可能致癌,也可能抑癌,具体取决于组织。目前对于 SIRT1 在非小细胞肺癌(NSCLC)中的作用知之甚少,非小细胞肺癌是最致命的癌症之一,通常与突变型 K-RAS 相关。因此,我们研究了 SIRT1 对 K-RAS 驱动的肺癌发生的影响。我们报告称,致癌性 K-RAS 通过 MEK 和 PI3K 依赖性途径下调小鼠胚胎成纤维细胞(MEFs)和人肺腺癌细胞系中的 SIRT1 蛋白水平。此外,Sirt1 在小鼠中的过表达可延迟 K-Ras 驱动的肺腺癌的出现,减少死亡时腺癌的数量和大小,并延长存活时间。一致地,较低水平的 SIRT1 与人类 NSCLC 患者的预后较差相关。从机制上讲,对 K-Ras 激活后不久分离的小鼠 Sirt1-Tg 肺细胞进行分析表明,Sirt1 过表达改变了与肿瘤发生相关的途径:增殖、凋亡或细胞外基质组织。我们的工作表明 SIRT1 在小鼠和人类 K-RAS 驱动的肺腺癌发展中具有抑癌作用,这表明 SIRT1-K-RAS 轴可能是 NSCLC 的治疗靶点。