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J. Biol. Chem., Vol. 278, Issue 29, 27287-27292, July 18, 2003

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Inhibition of Transcription Factor Stat5 Induces Cell Death of Human Prostate Cancer Cells^*

Tommi J. Ahonen   ¶, Jianwu Xie  ¶, Matthew J. LeBaron , Jianqiong Zhu , Martti Nurmi ||, Kalle Alanen **, Hallgeir Rui  and Marja T. Nevalainen  

From the Department of Oncology, Vincent T. Lombardi Cancer Center, Georgetown University Medical Center, Washington D. C. 20057, Department of Anatomy and Cell Biology, Institute of Biomedicine, University of Turku, Turku 20520, Finland, ^||Department of Surgery, University Hospital of Turku, Turku 20520, Finland, and ^**Department of Pathology, Institute of Biomedicine, University of Turku, Turku 20520, Finland

Identifying regulators of prostate cancer cell survival may lead to new therapeutic strategies for prostate cancer. We now report prevalent activation of transcription factor Stat5 in human prostate cancer and provide novel evidence that blocking activation of Stat5 in human prostate cancer cells leads to extensive cell death. Specifically, Stat5 was activated in 65% of human prostate cancer specimens examined based on nuclear location of tyrosine phosphorylated Stat5. Adenoviral gene delivery of a dominant-negative Stat5 mutant (DNStat5), but not wild-type Stat5, induced cell death of both the androgen-independent human prostate cancer cell line CWR22Rv and the androgen-sensitive LnCap cell line. Endogenous Stat5 was active in both CWR22Rv and LnCap cells. In contrast, only low levels of inactive Stat5 proteins were detected in the PC-3 cell line, which correlated with resistance to DNStat5-induced cell death. In CWR22Rv and LnCap cells, inhibition of Stat5 by expression of DNStat5 induced apoptotic cell death as judged from morphological changes, DNA fragmentation, and caspase-3 activation with evidence of a caspase-9-dependent mechanism. We propose that blocking Stat5 function may represent a novel therapeutic approach for prostate cancer.

Received for publication, April 24, 2003

^* This work was supported in part by National Institutes of Health Grants RO1 CA83813 and DK52013, Department of Defense Grant DAMD 17-01-1-0059, Turku University Graduate School of Biomedical Sciences (University of Turku, Turku, Finland), and the Foundation for the Finnish Cancer Institute. 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.

^¶ Both authors contributed equally to this work.

To whom correspondence should be addressed: Lombardi Cancer Center, Georgetown University, The Research Building E508, 3970 Reservoir Rd., N. W., Washington, D. C. 20057-1469. E-mail: mtn3{at}georgetown.edu.

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