Transcriptional repression and inhibition of nuclear translocation of androgen receptor by diallyl trisulfide in human prostate cancer cells.
OBJECTIVE
The present study was undertaken to determine the effect of diallyl trisulfide (DATS), a promising cancer chemopreventive constituent of garlic, on androgen receptor (AR) protein expression and function using prostate cancer cells.


METHODS
The protein levels of AR and prostate-specific antigen (PSA) were determined by immunoblotting. The effect of DATS treatment on AR mRNA level and AR promoter activity was determined by quantitative reverse transcription-PCR and luciferase reporter assay, respectively. Expression of AR protein in poorly differentiated carcinoma and normal prostate of transgenic adenocarcinoma of mouse prostate (TRAMP) mice was determined by immunohistochemistry. Confocal microscopy was done to determine nuclear translocation of AR. Cell viability was determined by trypan blue dye exclusion assay.


RESULTS
Exposure of prostate cancer cells (LNCaP, C4-2, and TRAMP-C1) to DATS resulted in a concentration-dependent decrease in protein level of AR, which was accompanied by suppression of intracellular and secreted levels of PSA. Structure-activity studies revealed critical roles for allyl groups and the oligosulfide chain length in DATS-mediated down-modulation of AR protein. Quantitative reverse transcription-PCR showed a dose-dependent decrease in AR mRNA level, which correlated with inhibition of AR promoter activity. DATS treatment inhibited synthetic androgen (R1881)-stimulated nuclear translocation of AR in LNCaP/C4-2 cells and proliferation of LNCaP cells. Oral gavage of 2 mg/day DATS (three times per week for 13 weeks) markedly suppressed AR protein level in poorly differentiated prostate cancer in TRAMP mice.


CONCLUSIONS
The present study shows, for the first time, that DATS treatment suppresses AR function in prostate cancer cells.
Stan
Silvia D
SD
Department of Pharmacology and Chemical Biology, and University of Pittsburgh Cancer Institute, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA.
Singh
Shivendra V
SV
D000498:Allyl Compounds / Q000494:pharmacology*; D059002:Androgen Receptor Antagonists; D000818:Animals; D016588:Anticarcinogenic Agents / Q000494:pharmacology*; D000975:Antioxidants / Q000494:pharmacology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D006801:Humans; D008297:Male; D051379:Mice; D017430:Prostate-Specific Antigen / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D011471:Prostatic Neoplasms / Q000378:metabolism* / Q000473:pathology; D011944:Receptors, Androgen / Q000235:genetics / Q000378:metabolism; D013440:Sulfides / Q000494:pharmacology*; D014158:Transcription, Genetic / Q000187:drug effects
D000498:Allyl Compounds; D059002:Androgen Receptor Antagonists; D016588:Anticarcinogenic Agents; D000975:Antioxidants; D011944:Receptors, Androgen; D013440:Sulfides; C042577:diallyl trisulfide; D017430:Prostate-Specific Antigen