IκB kinase overcomes PI3K/Akt and ERK/MAPK to control FOXO3a activity in acute myeloid leukemia

The FOXO transcription factors are involved in multiple signaling pathways and have tumor-suppressor functions. In acute myeloid leukemia (AML), deregulation of oncogenic kinases, including Akt, extra-signal–regulated kinase, or IκB kinase, is frequently observed, which may potentially inactivate FO...

Full description

Saved in:
Bibliographic Details
Published inBlood Vol. 116; no. 20; pp. 4240 - 4250
Main Authors Chapuis, Nicolas, Park, Sophie, Leotoing, Laurent, Tamburini, Jerome, Verdier, Frederique, Bardet, Valerie, Green, Alexa S., Willems, Lise, Agou, Fabrice, Ifrah, Norbert, Dreyfus, François, Bismuth, Georges, Baud, Veronique, Lacombe, Catherine, Mayeux, Patrick, Bouscary, Didier
Format Journal Article
LanguageEnglish
Published Washington, DC Elsevier Inc 18.11.2010
Americain Society of Hematology
American Society of Hematology
Subjects
Online AccessGet full text

Cover

Loading…
More Information
Summary:The FOXO transcription factors are involved in multiple signaling pathways and have tumor-suppressor functions. In acute myeloid leukemia (AML), deregulation of oncogenic kinases, including Akt, extra-signal–regulated kinase, or IκB kinase, is frequently observed, which may potentially inactivate FOXO activity. We therefore investigated the mechanism underlying the regulation of FOXO3a, the only FOXO protein constantly expressed in AML blast cells. We show that in both primary AML samples and in a MV4-11/FOXO3a-GFP cell line, FOXO3a is in a constant inactive state due to its cytoplasmic localization, and that neither PI3K/Akt nor extra-signal–regulated kinase–specific inhibition resulted in its nuclear translocation. In contrast, the anti-Nemo peptide that specifically inhibits IKK activity was found to induce FOXO3a nuclear localization in leukemic cells. Furthermore, an IKK-insensitive FOXO3a protein mutated at S644 translocated into the nucleus and activated the transcription of the Fas-L and p21Cip1 genes. This, in turn, inhibited leukemic cell proliferation and induced apoptosis. These results thus indicate that IKK activity maintains FOXO3a in the cytoplasm and establishes an important role of FOXO3a inactivation in the proliferation and survival of AML cells. The restoration of FOXO3a activity by interacting with its subcellular distribution may thus represent a new attractive therapeutic strategy for AML.
Bibliography:ObjectType-Article-1
SourceType-Scholarly Journals-1
ObjectType-Feature-2
content type line 23
ISSN:0006-4971
1528-0020
DOI:10.1182/blood-2009-12-260711