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

Nuclear FOXO proteins act as tumor suppressors by transcriptionally activating genes involved in apoptosis and cell cycle arrest, and these anticancer functions are inhibited by AKT‐induced phosphorylation and cytoplasmic sequestration of FOXOs. We found that, after AKT‐mediated phosphorylation at serine 319, FOXO1 binds to IQGAP1, a hub for activation of the MAPK pathway, and impedes IQGAP1‐dependent phosphorylation of ERK1/2 (pERK1/2). Conversely, decreased FOXO1 expression increases pERK1/2 in cancer cell lines and correlates with increased pERK1/2 levels in patient specimens and disease progression. Treatment of cancer cells with PI3K inhibitors or taxane causes FOXO1 localization in the nucleus, increased expression of pERK1/2, and drug resistance. These effects are reversed by administering a small FOXO1‐derived phospho‐mimicking peptide inhibitor in vitro and in mice. Our results show a tumor suppressor role of AKT‐phosphorylated FOXO1 in the cytoplasm and suggest that this function of FOXO1 can be harnessed to overcome chemoresistance in cancer. Synopsis AKT‐phosphorylated FOXO1 possesses a tumor suppressor function in the cytoplasm by binding to the scaffold protein IQGAP1, thereby inhibiting MAPK signaling. This role of FOXO1 can be exploited to overcome resistance to chemotherapies. AKT‐phosphorylated FOXO1 binds to IQGAP1—a hub for MAPK signaling—and impedes IQGAP1‐dependent phosphorylation of ERK1/2 (pERK1/2). Decreased FOXO1 expression induces an increase in pERK1/2 in cancer cell lines and correlates with increased pERK1/2 levels in patient specimens and with disease progression. Treatment of cancer cells with PI3K inhibitors or taxane causes FOXO1 localization in the nucleus, increased expression of pERK1/2, and drug resistance. Co‐treatment of cancer cells with a small FOXO1‐derived phospho‐mimicking peptide inhibitor overcomes chemoresistance in vitro and in mice. Graphical Abstract AKT‐phosphorylated FOXO1 possesses a tumor suppressor function in the cytoplasm by binding to the scaffold protein IQGAP1, thereby inhibiting MAPK signaling. This role of FOXO1 can be exploited to overcome resistance to chemotherapies.