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Molecular and Cellular Biology, January 2003, p. 104-118, Vol. 23, No. 1
0270-7306/03/$08.00+0     DOI: 10.1128/MCB.23.1.104-118.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

AKT-Independent Protection of Prostate Cancer Cells from Apoptosis Mediated through Complex Formation between the Androgen Receptor and FKHR

Pengfei Li,1 Heehyoung Lee,1 Shaodong Guo,2,{dagger} Terry G. Unterman,2 Guido Jenster,3 and Wenlong Bai1*

Department of Pathology, University of South Florida College of Medicine, and Program of Molecular Oncology and Drug Discovery, H. Lee Moffitt Cancer Center, Tampa, Florida 33612-4799,1 University of Illinois College of Medicine at Chicago and Chicago Area Veterans Healthcare System, Chicago, Illinois 60612,2 Department of Urology, Josephine Nefkens Institute, Eramus University Rotterdam, 3000 DR Rotterdam, The Netherlands3

Received 20 March 2002/ Returned for modification 6 May 2002/ Accepted 1 October 2002

Recent studies suggested that the protection of cell apoptosis by AKT involves phosphorylation and inhibition of FKHR and related FOXO forkhead transcription factors and that androgens provide an AKT-independent cell survival signal in prostate cancer cells. Here, we report receptor-dependent repression of FKHR function by androgens in prostate cancer cells. Transcriptional analysis demonstrated that activation of the androgen receptor caused an inhibition of both wild-type FKHR and a mutant in which all three known AKT sites were mutated to alanines, showing that the repression is AKT independent. In vivo and in vitro coprecipitation studies demonstrated that the repression is mediated through protein-protein interaction between FKHR and the androgen receptor. Mapping analysis localized the interacting domains to the carboxyl terminus between amino acids 350 and 655 of FKHR and to the amino-terminal A/B region and the ligand binding domain of the receptor. Further analysis demonstrated that the activated androgen receptor blocked FKHR's DNA binding activity and impaired its ability to induce Fas ligand expression and prostate cancer cell apoptosis and cell cycle arrest. These studies identify a new mechanism for androgen-mediated prostate cancer cell survival that appears to be independent of the activity of the receptor on androgen response element-mediated transcription and establish FKHR and related FOXO forkhead proteins as important nuclear targets for both AKT-dependent and -independent survival signals in prostate cancer cells.

* Corresponding author. Mailing address: Department of Pathology, University of South Florida College of Medicine, 12901 Bruce B. Downs Blvd., MDC 11 Tampa, FL 33612-4799. Phone: (813) 974-0563. Fax: (813) 974-5536. E-mail: wbai{at}hsc.usf.edu.

{dagger} Present address: Department of Molecular Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215.

Molecular and Cellular Biology, January 2003, p. 104-118, Vol. 23, No. 1
0022-538X/03/$08.00+0     DOI: 10.1128/MCB.23.1.104-118.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.



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