Testosterone regulation of homocysteine metabolism modulates redox status in human prostate cancer cells.
Clearance of homocysteine via the transsulfuration pathway provides an endogenous route for cysteine synthesis and represents a quantitatively significant source of this amino acid needed for glutathione synthesis. Men have higher plasma levels of total homocysteine than do women, but the mechanism of this sex-dependent difference is not known. In this study, we investigated regulation by testosterone of cystathionine beta-synthase (CBS), which catalyzes the committing step in the transsulfuration pathway. We report that testosterone downregulates CBS expression via a posttranscriptional mechanism in the androgen-responsive prostate cancer cell line, LNCaP. This diminution in CBS levels is accompanied by a decrease in flux through the transsulfuration pathway and by a lower intracellular glutathione concentration. The lower antioxidant capacity in testosterone-treated prostate cancer cells increases their susceptibility to oxidative stress conditions. These results demonstrate regulation of the homocysteine-clearing enzyme, CBS, by testosterone and suggest the potential utility of targeting this enzyme as a chemotherapeutic strategy.
Prudova
Anna
A
Redox Biology Center and the Biochemistry Department, University of Nebraska, Lincoln, Nebraska, USA.
Albin
Matthias
M
Bauman
Zachary
Z
Lin
Alexander
A
Vitvitsky
Victor
V
Banerjee
Ruma
R
D000230:Adenocarcinoma / Q000378:metabolism / Q000473:pathology; D000728:Androgens / Q000494:pharmacology*; D002384:Catalysis; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D003541:Cystathionine beta-Synthase / Q000032:analysis / Q000378:metabolism; D013196:Dihydrotestosterone / Q000494:pharmacology*; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects*; D017930:Genes, Reporter; D005978:Glutathione / Q000378:metabolism; D006710:Homocysteine / Q000378:metabolism*; D006801:Humans; D008156:Luciferases / Q000378:metabolism; D008297:Male; D010084:Oxidation-Reduction; D018384:Oxidative Stress / Q000187:drug effects; D011471:Prostatic Neoplasms / Q000378:metabolism* / Q000473:pathology; D011499:Protein Processing, Post-Translational; D013455:Sulfur / Q000378:metabolism; D013696:Temperature
D000728:Androgens; D013196:Dihydrotestosterone; D006710:Homocysteine; D013455:Sulfur; D008156:Luciferases; D003541:Cystathionine beta-Synthase; D005978:Glutathione