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J. Biol. Chem., Vol. 280, Issue 39, 33558-33565, September 30, 2005

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Induction of Androgen Receptor Expression by Phosphatidylinositol 3-Kinase/Akt Downstream Substrate, FOXO3a, and Their Roles in Apoptosis of LNCaP Prostate Cancer Cells^*

Lin Yang1, Shaozhen Xie1, Md. Saha Jamaluddin¶, Saleh Altuwaijri, Jing Ni, Eungseok Kim, Yei-Tsung Chen, Yueh-Chiang Hu, Liang Wang, Kuang-Hsiang Chuang, Chun-Te Wu||, and Chawnshang Chang2

From the George Whipple Laboratory for Cancer Research, the Departments of Pathology, Urology, and Radiation Oncology and The Cancer Center, University of Rochester, Rochester, New York 14642, the Department of Cancer Biology, M. D. Anderson Cancer Center, Houston, Texas 77054, the ^¶Department of Medicine, Section of Atherosclerosis, Baylor College of Medicine, Houston, Texas 77030, and the ^||Department of Urology, Chang Gung University and Memorial Hospital, Taipei 105, Taiwan

The phosphatidylinositol 3-kinase (PI3K)/Akt pathway plays important roles for prostate cancer cell survival, and the androgen receptor (AR) plays essential roles for prostate cancer cell proliferation. How these two signals cooperate to control cell growth and death, however, remains unclear and debated. Here we provide the first linkage by the identification of Forkhead transcription factor FOXO3a, the PI3K/Akt downstream substrate, as a positive regulator for the induction of AR gene expression. Both Western blot and real time PCR assays demonstrate that FOXO3a can induce AR expression at the protein and mRNA levels, and gel shift and chromatin immunoprecipitation assays further demonstrate that FOXO3a can induce 5' AR promoter activity via binding to the consensus DNA-binding sequence in the AR 5' promoter -1290 to -1297 (5'-TTGTTTCA-3'). Under normal growth conditions, blocking PI3K/Akt signals by LY294002 causes LNCaP cell arrest in G₁ phase rather than apoptosis. However, further blocking of AR functions by AR small interfering RNA leads to dramatic LNCaP cell death, suggesting that AR may play important protective roles when the PI3K/Akt signal pathway is blocked by LY294002. Together, our data provide the first model to explain how PI3K/Akt and AR can cooperate to control LNCaP cell growth and death under normal conditions.

Received for publication, April 25, 2005 , and in revised form, July 26, 2005.

^* This work was supported by National Institutes of Health Grants CA55639, CA71870, DK67686, and DK60948, the George Whipple Professorship Endowment, and Dr. Shu-Shi Chang Neuroendocrinology Fund. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ Both authors contributed equally to this work.

² To whom correspondence should be addressed. Tel.: 585-275-9994; E-mail: Chang{at}urmc.rochester.edu.

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