AKT-phosphorylated FOXO1 suppresses ERK activation and chemoresistance by disrupting IQGAP1-MAPK interaction |
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| Authors: | Chun-Wu Pan Haojie Huang Chun-Wu Pan Xin Jin Yu Zhao Yunqian Pan Jing Yang R Jeffrey Karnes Jun Zhang Liguo Wang Haojie Huang |
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| Affiliation: | 1. Department of Urology, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China;2. Department of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, MN, USA |
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| Abstract: | 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. |
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| Keywords: | FOXO1 AKT MAPK chemoresistance cancer |
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