Androgen receptor signaling intensity is a key factor in determining the sensitivity of prostate cancer cells to selenium inhibition of growth and cancer-specific biomarkers.

Abstract

Our previous report showed that methylseleninic acid (MSA) significantly decreases the expression of androgen receptor and prostate-specific antigen (PSA) in LNCaP cells. The present study extended the above observations by showing the universality of this phenomenon and that the inhibitory effect of MSA on prostate cancer cell growth and cancer-specific biomarkers is mediated through androgen receptor down-regulation. First, MSA decreases the expression of androgen receptor and PSA in five human prostate cancer cell lines (LNCaP, LAPC-4, CWR22Rv1, LNCaP-C81, and LNCaP-LN3), irrespective of their androgen receptor genotype (wild type versus mutant) or sensitivity to androgen-stimulated growth. Second, by using the ARE-luciferase reporter gene assay, we found that MSA suppression of androgen receptor transactivation is accounted for primarily by the reduction of androgen receptor protein level. Third, MSA inhibition of five androgen receptor-regulated genes implicated in prostate carcinogenesis (PSA, KLK2, ABCC4, DHCR24, and GUCY1A3) is significantly attenuated by androgen receptor overexpression. Fourth, transfection of androgen receptor in LNCaP cells weakened noticeably the inhibitory effect of MSA on cell growth and proliferation. Androgen receptor signaling has been documented extensively to play an important role in the development of both androgen-dependent and -independent prostate cancer. Our finding that MSA reduces androgen receptor availability by blocking androgen receptor transcription provides justification for a mechanism-driven intervention strategy in using selenium to control prostate cancer progression.

• Authors: Yan Dong, Haitao Zhang, Allen C Gao, James R Marshall, Clement Ip
• Journal: Molecular cancer therapeutics (Mol Cancer Ther) Vol. 4 Issue 7 Pg. 1047-55 (Jul 2005) ISSN: 1535-7163 [Print] United States
• PMID: 16020662 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S., Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Biomarkers, Tumor
• Organoselenium Compounds
• Receptors, Androgen
• methylselenic acid
• Luciferases
• Selenium

Topics

• Biomarkers, Tumor (metabolism)
• Cell Proliferation
• Down-Regulation
• Gene Expression Regulation, Neoplastic
• Genes, Reporter
• Humans
• Luciferases (drug effects, genetics, metabolism)
• Male
• Organoselenium Compounds (pharmacology)
• Prostatic Neoplasms (drug therapy, metabolism, pathology)
• Receptors, Androgen (drug effects, genetics, metabolism)
• Selenium (pharmacology)
• Signal Transduction
• Transcription, Genetic
• Tumor Cells, Cultured