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A more recent version of this article appeared on February 1, 2004
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Submitted on July 17, 2003
Revised on October 14, 2003
Accepted on October 17, 2003
1 Department of Urology, Stanford University School of Medicine, Stanford, California 94305
2 Department of Genetics, Stanford University School of Medicine, Stanford, California 94305
3 Department of Hematology, Stanford University School of Medicine, Stanford, California 94305
4 James D. Brooks, Department of Urology, Room S287, Stanford University Medical Center, 300 Pasteur Drive, Stanford,
CA 94305-5118
* Corresponding author. E-mail address: jdbrooks{at}stanford.edu.
Methylseleninic acid (MSA) has been shown to have potent anticancer activity, and is an excellent compound for studying the anticancer effects of selenium in vitro. To gain insights into the effects of MSA in prostate cancer, we characterized the global transcriptional response of LNCaP, an androgen-sensitive human prostate cancer cell line, to MSA using high-density cDNA microarrays. We identified 951 genes whose expression shows striking dose- and time-dependent changes in response to 3-30 µM MSA over the time course of 48 h. Transcript levels of many cell cycle-regulated genes change in response to MSA suggesting that MSA inhibits proliferation. Consistent with these gene expression changes, cell proliferation, monitored by carboxyfluoroscein succinimidyl ester (CFSE) staining, was decreased after MSA treatment, and an accumulation of cells at G0/G1 phase was detected by flow cytometry. Surprisingly, MSA also modulated expression of many androgen-regulated genes, suppressed androgen receptor (AR) expression at both mRNA and protein level, and decreased levels of prostate specific antigen (PSA) secreted into the medium. Low concentrations of MSA also induced significant increases in transcript levels of phase 2 detoxification enzymes, and induced NAD(P)H dehydrogenase, quinone 1 (NQO1) enzymatic activity, a surrogate marker of global phase 2 enzyme activity. Our results suggest that MSA may protect against prostate cancer by inhibiting cell proliferation, by modulating the expression of AR and AR-regulated genes and by inducing carcinogen defenses.
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