Inhibition of androgen receptor signaling by selenite and methylseleninic acid in prostate cancer cells: two distinct mechanisms of action.
The development of prostate cancer and its progression to a hormone-refractory state is highly dependent on androgen receptor (AR) expression. Recent studies have shown that the selenium-based compound methylseleninic acid (MSeA) can disrupt AR signaling in prostate cancer cells. We have found that selenite can inhibit AR expression and activity in LAPC-4 and LNCaP prostate cancer cells as well but through a different mechanism. On entering the cell, selenite consumes reduced glutathione (GSH) and generates superoxide radicals. Pretreatment with N-acetylcysteine, a GSH precursor, blocked the down-regulation of AR mRNA and protein expression by selenite and restored AR ligand binding and prostate-specific antigen expression to control levels. MSeA reacts with reduced GSH within the cell; however, N-acetylcysteine did not effect MSeA-induced down-regulation of AR and prostate-specific antigen. The superoxide dismutase mimetic MnTMPyP was also found to prevent the decrease in AR expression caused by selenite but not by MSeA. A Sp1-binding site in the AR promoter is a key regulatory component for its expression. Selenite decreased Sp1 expression and activity, whereas MSeA did not. The inhibition of Sp1 by selenite was reversed in the presence of N-acetylcysteine. In conclusion, we have found that selenite and MSeA disrupt AR signaling by distinct mechanisms. The inhibition of AR expression and activity by selenite occurs via a redox mechanism involving GSH, superoxide, and Sp1.
Husbeck
Bryan
B
Department of Radiation Oncology, Stanford University Medical Center, 300 Pasteur Drive, CA 94305, USA.
Bhattacharyya
Rumi S
RS
Feldman
David
D
Knox
Susan J
SJ
D000111:Acetylcysteine / Q000494:pharmacology; D059002:Androgen Receptor Antagonists; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation; D005978:Glutathione / Q000378:metabolism; D006801:Humans; D008297:Male; D008665:Metalloporphyrins / Q000494:pharmacology; D015741:Metribolone / Q000494:pharmacology; D016566:Organoselenium Compounds / Q000494:pharmacology*; D017430:Prostate-Specific Antigen / Q000187:drug effects / Q000378:metabolism; D011471:Prostatic Neoplasms / Q000188:drug therapy / Q000378:metabolism*; D011944:Receptors, Androgen / Q000378:metabolism*; D011987:Receptors, Steroid / Q000187:drug effects / Q000378:metabolism; D015398:Signal Transduction; D018038:Sodium Selenite / Q000494:pharmacology*; D016329:Sp1 Transcription Factor / Q000187:drug effects / Q000378:metabolism; D013481:Superoxides / Q000378:metabolism; D014407:Tumor Cells, Cultured
D059002:Androgen Receptor Antagonists; D008665:Metalloporphyrins; C502230:Mn(III) 5,10,15,20-tetrakis(N-methylpyridinium-2-yl)porphyrin; D016566:Organoselenium Compounds; D011944:Receptors, Androgen; D011987:Receptors, Steroid; D016329:Sp1 Transcription Factor; D013481:Superoxides; D015741:Metribolone; C008493:methylselenic acid; D017430:Prostate-Specific Antigen; D005978:Glutathione; D018038:Sodium Selenite; D000111:Acetylcysteine