Inhibition of fatty acid synthase activity in prostate cancer cells by dutasteride.
OBJECTIVE
With malignant progression to androgen independence, prostate cancer cells develop resistance to apoptosis and exhibit a variety of gene expression changes, including increased fatty acid synthase (FASN) expression. Increased FASN expression has been shown to correlate with poor prognosis, and correspondingly, the FASN gene has been proposed as a therapeutic target. Because FASN is an androgen regulated gene in the prostate, we have examined the effects of dutasteride on FASN in prostate cancer cells in vitro. Dutasteride is a novel dual inhibitor of the 5 alpha-reductase enzymes and is currently in use both for treatment of benign prostate hyperplasia (BPH) and in the reduction by dutasteride of prostate cancer events (REDUCE) prostate cancer prevention trial.


METHODS
Microarray analysis was used to identify genes affected by treatment with dutasteride, followed by real time PCR confirmation. FASN expression at the protein level was examined using Western blotting and immunocytochemistry. Enzymatic activity of FASN was assayed by (14)C-labeled malonyl-CoA incorporation. Viability after dutasteride treatment was assayed by MTS (Promega) and apoptosis via caspase 3/7 by DEVD cleavage assay.


RESULTS
We have demonstrated that the 5 alpha-reductase inhibitor dutasteride, at clinically relevant levels, inhibits FASN mRNA, protein expression and enzymatic activity in prostate cancer cells.


CONCLUSIONS
This is the first study to examine the effects of clinically relevant levels of dutasteride on prostate cancer cells at the molecular level and specifically, demonstrating the inhibition of FASN in these cells.
Schmidt
Lucy J
LJ
Department of Urology Research, Mayo Clinic College of Medicine, Mayo Clinic, Rochester, Minnesota 55905, USA.
Ballman
Karla V
KV
Tindall
Donald J
DJ
D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D001378:Azasteroids / Q000494:pharmacology*; D053148:Caspase 3 / Q000378:metabolism; D053179:Caspase 7 / Q000378:metabolism; D045744:Cell Line, Tumor; D042944:Cholestenone 5 alpha-Reductase / Q000235:genetics / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D000068538:Dutasteride; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D064429:Fatty Acid Synthases / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects / Q000502:physiology; D006801:Humans; D008297:Male; D011471:Prostatic Neoplasms / Q000201:enzymology* / Q000473:pathology; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D051779:Sterol Regulatory Element Binding Proteins / Q000502:physiology
D001378:Azasteroids; D004791:Enzyme Inhibitors; D012333:RNA, Messenger; D051779:Sterol Regulatory Element Binding Proteins; D042944:Cholestenone 5 alpha-Reductase; D064429:Fatty Acid Synthases; D053148:Caspase 3; D053179:Caspase 7; D000068538:Dutasteride