DEPTOR inhibits lung tumorigenesis by inactivating the EGFR-mTOR signals

Area of Science:

• Oncology
• Molecular Biology
• Cell Signaling

Background:

• DEPTOR regulates mTORC1/2 activity, impacting cell proliferation and survival.
• The role of DEPTOR in lung tumorigenesis and its clinical significance are not well understood.

Purpose of the Study:

• To investigate the physiological role and clinical significance of DEPTOR in lung cancer.
• To elucidate the molecular mechanisms by which DEPTOR influences lung tumor progression.

Main Methods:

• Analysis of DEPTOR expression in lung cancer patient samples.
• In vitro studies using human lung cancer cells to assess the effects of DEPTOR depletion on proliferation, survival, migration, and invasion.
• In vivo studies using a mouse model of lung cancer (KrasG12D;p53fl/fl) with Deptor deletion.
• Western blotting and molecular assays to examine signaling pathways, including EGFR and mTOR.

Main Results:

• Decreased DEPTOR expression correlates with larger tumor size, poor differentiation, and reduced survival in lung cancer patients.
• DEPTOR depletion enhances proliferation, survival, migration, and invasion of lung cancer cells.
• DEPTOR inactivates EGFR signaling and directly modulates mTORC1/2 activity. Loss of DEPTOR activates both EGFR and mTOR pathways.
• Activated EGFR-mTOR signaling upregulates ZEB1 and SLUG, promoting epithelial-mesenchymal transition (EMT).
• Deptor deletion accelerates KrasG12D;p53fl/fl-induced lung tumorigenesis and shortens survival in mice.

Conclusions:

• DEPTOR functions as a tumor suppressor in lung cancer.
• Reduced DEPTOR expression promotes lung cancer progression through EGFR-mTOR pathway activation and EMT.
• DEPTOR is a potential therapeutic target for lung cancer treatment.