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Molecular and Cellular Biology, October 2008, p. 5886-5898, Vol. 28, No. 19
0270-7306/08/$08.00+0     doi:10.1128/MCB.01265-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

The Forkhead Transcription Factor FOXO3a Increases Phosphoinositide-3 Kinase/Akt Activity in Drug-Resistant Leukemic Cells through Induction of PIK3CA Expression{triangledown}

Rosaline C.-Y. Hui ,1,{dagger},{ddagger} Ana R. Gomes,1,{dagger} Demetra Constantinidou,1 Joana R. Costa,1 Christina T. Karadedou,1 Silvia Fernandez de Mattos,1,§ Matthias P. Wymann,2 Jan J. Brosens,3 Almut Schulze,4 and Eric W.-F. Lam1*

Cancer Research-UK Labs, Department of Oncology, MRC Cyclotron Building, Imperial College London, Hammersmith Hospital Campus, Du Cane Road, London W12 0NN, United Kingdom,1 Department of Clinical and Biological Sciences, Institute of Biochemistry and Genetics, Centre of Biomedicine, University of Basel, Mattenstrasse 28, CH-4058 Basel, Switzerland,2 Institute of Reproductive and Developmental Biology, Hammersmith Hospital Campus, Du Cane Road, London W12 0NN, United Kingdom,3 Gene Expression Analysis Laboratory, Cancer Research UK London Research Institute, 44 Lincoln's Inn Fields, London WC2A 3PX, United Kingdom4

Received 15 July 2007/ Returned for modification 19 August 2007/ Accepted 13 July 2008

The phosphoinositide-3 kinase (PI3K)/Akt signal pathway plays a key role in the tumorigenesis of many cancers and in the subsequent development of drug resistance. Using the K562 chronic myelogenous leukemia (CML) cell line and the doxorubicin-resistant derivative lines KD30 and KD225 as models, we observed that enhanced PI3K/Akt activity and the acquisition of chemoresistance correlated unexpectedly with the increased expression and nuclear accumulation of FOXO3a. Moreover, we found that the induction of FOXO3a activity in naïve K562 cells was sufficient to enhance PI3K/Akt activity and to confer resistance to the cytotoxic effects of doxorubicin. Conversely, the knockdown of endogenous FOXO3a expression reduced PI3K/Akt activity and sensitized these cells to doxorubicin. Further chromatin immunoprecipitation and promoter mutation analyses demonstrated that FOXO3a regulates the expression of the PI3K catalytic subunit p110{alpha} through the activation of a promoter region proximal to a novel untranslated exon upstream from the reported transcription start site of the p110{alpha} gene PIK3CA. As was the case for FOXO3a, the expression or knockdown of p110{alpha} was sufficient to amplify or reduce PI3K/Akt activity, respectively. Thus, our results suggest that the chronic activation of FOXO3a by doxorubicin in CML cells can enhance survival through a feedback mechanism that involves enhanced p110{alpha} expression and hyperactivation of the PI3K/Akt pathway.

* Corresponding author. Mailing address: Cancer Research-UK Laboratories, Department of Oncology, MRC Cyclotron Building, Imperial College London, Hammersmith Hospital, Du Cane Road, London W12 0NN, United Kingdom. Phone: 44-20-8383-5829. Fax: 44-20-8383-5830. E-mail: eric.lam{at}imperial.ac.uk

{triangledown} Published ahead of print on 21 July 2008.

{dagger} R.C.-Y.H. and A.R.G. contributed equally to the work.

{ddagger} Present address: Department of Dermatology, Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Taipei, Taiwan.

§ Present address: Grup de Biologia Cellular del Càncer i Oncologia Traslacional, Institut Universitari d'Investigacions en Ciències de la Salut, Dept. Biologia Fonamental, Universitat Illes Balears, Crta. Valldemossa km 7.5, 07122 Palma, Illes Balears, Spain.

Molecular and Cellular Biology, October 2008, p. 5886-5898, Vol. 28, No. 19
0270-7306/08/$08.00+0     doi:10.1128/MCB.01265-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.



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