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Sirt1 protects from K-Ras-driven lung carcinogenesis

Luis Filipe Costa-Machado1, Roberto Martín-Hernández2, Miguel Ángel Sanchez-Luengo3

  • 1Bioactive Products and Metabolic Syndrome Group - BIOPROMET, Madrid Institute for Advanced Studies - IMDEA Food, CEI UAM+CSIC, Madrid, Spain.

EMBO Reports
|July 20, 2018
PubMed

Insights

SIRT1 acts as a tumor suppressor in K-RAS-driven lung cancer. Overexpressing SIRT1 delays tumor formation and improves survival in mouse models, suggesting a therapeutic target for non-small cell lung carcinoma.

Area of Science:

  • Oncology
  • Molecular Biology
  • Biochemistry

Background:

  • The NAD+-dependent deacetylase SIRT1 exhibits context-dependent roles in cancer, acting as either oncogenic or tumor suppressive.
  • The function of SIRT1 in non-small cell lung carcinoma (NSCLC), a prevalent and lethal cancer often linked to K-RAS mutations, remains largely uncharacterized.

Purpose of the Study:

  • To investigate the role of SIRT1 in K-RAS-driven lung carcinogenesis.
  • To elucidate the impact of SIRT1 on the development and progression of non-small cell lung carcinoma.

Main Methods:

  • Investigated SIRT1 protein levels in mouse embryo fibroblasts and human lung adenocarcinoma cell lines with oncogenic K-RAS.
  • Utilized Sirt1 overexpression mouse models to assess the effect on K-RasG12V-driven lung adenocarcinoma development and survival.
  • Analyzed molecular pathways altered by Sirt1 overexpression in isolated mouse pneumocytes following K-RasG12V activation.

Main Results:

  • Oncogenic K-RAS downregulates SIRT1 protein levels in a MEK and PI3K-dependent manner.
  • Sirt1 overexpression in mice significantly delays K-RasG12V-driven lung adenocarcinoma formation, reducing tumor burden and extending survival.
  • Lower SIRT1 levels correlate with poorer prognosis in human NSCLC patients.

Conclusions:

  • SIRT1 demonstrates a tumor suppressive function in the context of K-RAS-driven lung adenocarcinoma.
  • The SIRT1-K-RAS axis represents a potential therapeutic target for non-small cell lung carcinoma.
Keywords:
K‐RASSIRT1non‐small cell lung carcinoma

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