Rutgers Cancer Institute of New Jersey, Rutgers, The State University of New Jersey, New Brunswick, NJ, USA.
Department of Pharmacology, Robert Wood Johnson Medical School, Rutgers, The State University of New Jersey, Piscataway, NJ, USA.
Nat Commun. 2021 Apr 15;12(1):2259. doi: 10.1038/s41467-021-22480-x.
SOD1 is known as the major cytoplasmic superoxide dismutase and an anticancer target. However, the role of SOD1 in cancer is not fully understood. Herein we describe the generation of an inducible Sod1 knockout in KRAS-driven NSCLC mouse model. Sod1 knockout markedly reduces tumor burden in vivo and blocks growth of KRAS mutant NSCLC cells in vitro. Intriguingly, SOD1 is enriched in the nucleus and notably in the nucleolus of NSCLC cells. The nuclear and nucleolar, not cytoplasmic, form of SOD1 is essential for lung cancer cell proliferation. Moreover, SOD1 interacts with PeBoW complex and controls its assembly necessary for pre-60S ribosomal subunit maturation. Mechanistically, SOD1 regulates co-localization of PeBoW with and processing of pre-rRNA, and maturation of cytoplasmic 60S ribosomal subunits in KRAS mutant lung cancer cells. Collectively, our study unravels a nuclear SOD1 function essential for ribosome biogenesis and proliferation in KRAS-driven lung cancer.
SOD1 被称为主要的细胞质超氧化物歧化酶和抗癌靶点。然而，SOD1 在癌症中的作用尚不完全清楚。在此，我们描述了在 KRAS 驱动的 NSCLC 小鼠模型中诱导型 Sod1 敲除的产生。Sod1 敲除显著减少体内肿瘤负担，并阻断 KRAS 突变型 NSCLC 细胞的体外生长。有趣的是，SOD1 在 NSCLC 细胞的核内富集，尤其是在核仁中。SOD1 的核内和核仁形式，而不是细胞质形式，对肺癌细胞增殖至关重要。此外，SOD1 与 PeBoW 复合物相互作用，并控制其组装，这对于 pre-60S 核糖体亚基成熟是必需的。在机制上，SOD1 调节 PeBoW 与 pre-rRNA 的共定位和处理，以及 KRAS 突变型肺癌细胞中细胞质 60S 核糖体亚基的成熟。总之，我们的研究揭示了核 SOD1 在 KRAS 驱动的肺癌中核糖体生物发生和增殖所必需的功能。
