RhoB loss induces Rac1-dependent mesenchymal cell invasion in lung cells through PP2A inhibition.

Area of Science:

• Oncology
• Cell Biology
• Molecular Mechanisms

Background:

• Non-small-cell lung cancer (NSCLC) is a leading cause of cancer mortality, largely due to metastasis.
• Understanding the molecular mechanisms of cancer cell detachment and migration is crucial for developing effective treatments.

Purpose of the Study:

• To identify key regulators of bronchial cell morphology in three-dimensional (3D) matrices.
• To elucidate the role of the small GTPase RhoB in non-small-cell lung cancer progression and metastasis.

Main Methods:

• Investigated RhoB's role in bronchial cell morphology using 3D matrix cultures.
• Analyzed epithelial-mesenchymal transition (EMT) markers, including Slug and E-cadherin.
• Examined signaling pathways involving Akt1, Rac1, Trio, and protein phosphatase 2A (PP2A) with its subunit B55.

Main Results:

• Loss of RhoB induced EMT, characterized by increased cell invasiveness and elongated cell morphology in 3D cultures.
• RhoB loss led to Slug induction, E-cadherin repression, and activation of the Akt1-Trio-Rac1 pathway.
• RhoB positively regulated PP2A activity via B55 recruitment, which was essential for Akt dephosphorylation and suppression of invasiveness.

Conclusions:

• RhoB acts as a tumor suppressor in lung cancer by inhibiting EMT-derived invasiveness.
• A novel signaling axis involving RhoB, PP2A, and Akt dephosphorylation is identified.
• Targeting this pathway could offer new strategies for preventing early metastatic dissemination in NSCLC.