5 alpha-reductase inhibitor Dutasteride inhibits fatty acid synthase activity in prostate cancer cells.

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While androgen ablation therapy remains the main treatment for advanced prostate cancer, the overall survival rate is only two to three years from initiation. The success of androgen ablation therapy is often terminated by the emergence of androgen-depletion-independent (ADI) disease. 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 expression. Dutasteride is a novel dual inhibitor of the 5 alpha-reductase isoenzymes which convert testosterone to the more potent dihydrotestosterone in prostate cells. It is currently in use clinically both for treatment of benign prostate hyperplasia (BPH) and in the REDUCE prostate cancer prevention trial. Previously, we have shown that dutasteride causes cell death in LNCaP prostate cancer cells both in the presence or absence of androgens, indicating that dutasteride is affecting more than the androgen pathway via reduction in DHT levels by inhibition of 5-alpha-reductase. For this reason we sought to delineate other genes and pathways that might be involved by treating LNCaP cells with dutasteride and performing microarray analysis. In this report, we have treated prostate cancer cells with clinically relevant levels of dutasteride and monitored genes and pathways affected by microarray analysis. One gene that was markedly down-regulated by dutasteride treatment was fatty acid synthase (FASN). FASN is an androgen-regulated enzyme involved in lipogenesis. In prostate cancer, increased FASN expression has been shown to correlate with poor prognosis and correspondingly, the FASN gene has been proposed as a therapeutic target. We have demonstrated that the 5 alpha-reductase inhibitor dutasteride, at clinically relevant levels, inhibits FASN mRNA, protein expression and enzyme activity in prostate cancer cells.