SOD1 regulates ribosome biogenesis in KRAS mutant non-small cell lung cancer
Xiaowen Wang1,2,3, Hong Zhang1,2, Russell Sapio4
1Rutgers Cancer Institute of New Jersey, Rutgers, The State University of New Jersey, New Brunswick, NJ, USA.
Abstract:
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.
Insights
Nuclear superoxide dismutase 1 (SOD1) is crucial for KRAS-driven lung cancer cell growth by regulating ribosome biogenesis. Knocking out SOD1 significantly reduces tumor burden and blocks cancer cell proliferation.
Area of Science:
- Molecular Biology
- Oncology
- Cell Biology
Background:
- Superoxide dismutase 1 (SOD1) is a key antioxidant enzyme.
- Its precise role in cancer, particularly non-small cell lung cancer (NSCLC), remains incompletely understood.
- SOD1 is a potential anticancer target.
Purpose of the Study:
- To investigate the function of SOD1 in KRAS-driven NSCLC.
- To elucidate the specific mechanisms by which SOD1 influences lung cancer cell proliferation.
Main Methods:
- Generation of an inducible Sod1 knockout in a KRAS-driven NSCLC mouse model.
- In vitro and in vivo assessment of tumor burden and cell growth.
- Subcellular localization studies of SOD1.
- Analysis of SOD1 interaction with the PeBoW complex and its role in ribosome biogenesis.
Main Results:
- Sod1 knockout significantly reduced tumor burden in vivo and inhibited KRAS mutant NSCLC cell growth in vitro.
- SOD1 was found to be enriched in the nucleus and nucleolus of NSCLC cells.
- Nuclear/nucleolar SOD1, not cytoplasmic, was essential for lung cancer cell proliferation.
- SOD1 interacts with the PeBoW complex, controlling its assembly and pre-60S ribosomal subunit maturation.
- SOD1 regulates pre-ribosomal RNA processing and cytoplasmic 60S ribosomal subunit maturation.
Conclusions:
- Nuclear SOD1 plays a critical role in ribosome biogenesis and proliferation in KRAS-driven NSCLC.
- This study reveals a novel nuclear function of SOD1 essential for lung cancer cell survival.
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