AKT-phosphorylated FOXO1 suppresses ERK activation and chemoresistance by disrupting IQGAP1-MAPK interaction

Area of Science:

• Oncology
• Molecular Biology
• Cell Signaling

Background:

• FOXO proteins are tumor suppressors that induce apoptosis and cell cycle arrest.
• AKT signaling phosphorylates FOXO proteins, leading to their cytoplasmic sequestration and inhibition of tumor suppressor functions.
• The interaction between FOXO1 and IQGAP1 in the context of cancer and drug resistance is not well understood.

Purpose of the Study:

• To investigate the role of AKT-mediated phosphorylation of FOXO1 in regulating the MAPK pathway.
• To determine the impact of FOXO1-IQGAP1 interaction on cancer cell proliferation and drug resistance.
• To explore the therapeutic potential of targeting the FOXO1-IQGAP1 interaction to overcome chemoresistance.

Main Methods:

• Western blotting to detect protein phosphorylation (pERK1/2) and expression.
• Immunoprecipitation to study protein-protein interactions (FOXO1-IQGAP1).
• Cell culture experiments with PI3K inhibitors and taxane treatment.
• In vitro and in vivo studies using a FOXO1-derived phospho-mimicking peptide inhibitor.

Main Results:

• AKT-mediated phosphorylation of FOXO1 at serine 319 promotes binding to IQGAP1.
• FOXO1 binding to IQGAP1 inhibits IQGAP1-dependent ERK1/2 phosphorylation (pERK1/2).
• Reduced FOXO1 expression or PI3K inhibitor/taxane treatment increases pERK1/2 and leads to drug resistance.
• A FOXO1-derived peptide inhibitor reversed these effects, restoring nuclear FOXO1 localization and chemosensitivity.

Conclusions:

• Cytoplasmic AKT-phosphorylated FOXO1 acts as a tumor suppressor by inhibiting the MAPK pathway.
• The FOXO1-IQGAP1 interaction is a critical mechanism by which FOXO1 suppresses tumor growth.
• Targeting this interaction with specific inhibitors holds promise for overcoming chemoresistance in cancer.