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EMBO J. 2017 Apr 13;36(8):995-1010. doi: 10.15252/embj.201695534. Epub 2017 Mar 9.

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

Author information

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.
3
Department of Urology, Mayo Clinic, Rochester, MN, USA.
4
Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA.
5
Division of Biomedical Statistics and Informatics, Mayo Clinic, Rochester, MN, USA.
6
Department of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, MN, USA huang.haojie@mayo.edu.
7
Mayo Clinic Cancer Center, Mayo Clinic, Rochester, MN, USA.

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.

KEYWORDS:

AKT; FOXO1; MAPK; cancer; chemoresistance

PMID:
28279977
PMCID:
PMC5391142
DOI:
10.15252/embj.201695534
[Indexed for MEDLINE]
Free PMC Article

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