Journal
EMBO JOURNAL
Volume 36, Issue 8, Pages 995-1010Publisher
WILEY
DOI: 10.15252/embj.201695534
Keywords
FOXO1; AKT; MAPK; chemoresistance; cancer
Categories
Funding
- National Institutes of Health [CA134514, CA130908, CA193239]
- Department of Defense [W81XWH-09-1-622, W81XWH-14-1-0486]
- Mayo Clinic Center for Individualized Medicine
- National Natural Science Foundation of China [81101931]
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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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