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¹ Hormel Institute, University of Minnesota, Austin, Minnesota; ² College of Veterinary Medicine, Seoul National University, Seoul, Korea; ³ Roswell Park Cancer Institute, Buffalo, New York; and ⁴ Mayo Clinic and Foundation, Rochester, Minnesota

Requests for Reprints: Junxuan Lü, Hormel Institute, University of Minnesota, 801 16th Avenue NE, Austin, MN 55912. Phone: (507) 437-9680; Fax: (507) 437-9606. E-mail: jlu{at}hi.umn.edu

Prostate-specific antigen (PSA) is widely used clinically for prostate cancer diagnostics and as an indicator of therapeutic efficacy and recurrence. Several human chemoprevention trials are being conducted to validate the prostate cancer prevention efficacy of selenium and PSA is used in these trials as a biomarker of response. A better understanding of the effects of selenium metabolites on the kinetics of PSA turnover and secretion in prostate cancer cells treated with selenium at concentrations which are achievable physiologically will be important for interpreting the results of these trials. This study addresses whether the putative active anticancer selenium metabolite methylselenol or its precursor methylseleninic acid (MSeA) specifically inhibits PSA expression in the androgen-responsive LNCaP prostate cancer cell model. The results show that exposure to sub-apoptotic concentrations of MSeA and methylselenol inhibited PSA protein expression and secretion, whereas sodium selenite and selenomethionine lacked inhibitory effect. The inhibition was detectable at 3 h of exposure and required a threshold level of MSeA to sustain. Turnover experiments showed that MSeA caused rapid PSA degradation, which was partially blocked by lysosomal inhibitors, but not by a proteasomal inhibitor. Furthermore, MSeA treatment reduced PSA mRNA level, down-regulated androgen receptor protein expression, and inhibited androgen-stimulated PSA promoter transcription. In summary, methylselenol or MSeA specifically and rapidly inhibited PSA expression through two mechanisms of action: inducing PSA protein degradation and suppressing androgen-stimulated PSA transcription. These findings may have important mechanistic implications for the prostate specific cancer chemopreventive action of selenium.

Key Words: selenium • methylselenol • methylseleninic acid • selenomethionine • prostate cancer • PSA • LNCaP

Grant support: The Hormel Foundation and grants from Department of Defense Prostate Cancer Research Program (DAMD17-02-1-0007 to J. Lü) and National Cancer Institute (CA92231 to J. Lü, CA88900 to C.Y.F. Young, and CA91990 to C. Ip). S.D. Cho was supported by a graduate fellowship from Seoul National University, Korea.

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.

Note: The University of Minnesota is an equal opportunity educator and employer.

Received 12/12/03; revised 2/25/04; accepted 3/ 9/04.