Increased fatty acid synthase as a therapeutic target in androgen-independent prostate cancer progression

BACKGROUND. Fatty acid synthase (FAS) performs the anabolic conversion of d ietary carbohydrate or protein to fat. FAS expression is low in most normal tissues, but is elevated in many human cancers, including androgen-sensiti ve and androgen-independent prostate cancer. METHODS. Immunohistochemical evaluation of FAS expression was performed in human prostate cancer specimens under various states of androgen ablation. in vitro and in vivo prostate cancer models were evaluated for FAS expressi on and activity under androgenic and androgen-depleted conditions, and were tested for sensitivity to antimetabolite drugs that target fatty acid synt hesis. RESULTS. While FAS expression in the prostate was androgen responsive, it p ersisted or was reactivated in human prostate carcinoma after androgen abla tion, and was high in 82% of lethal tumors examined at autopsy. Similar pat terns of FAS expression and fatty acid synthesis were seen in cell culture and xenograft models of human prostate cancer. Pharmacologic inhibition of FAS resulted in a dose-dependent reduction of tumor growth in these models, including fourfold inhibition of an androgen-independent human prostate ca ncer xenograft with little associated toxicity. CONCLUSIONS. The data suggest that FAS expression/FA synthesis provides an important functional aspect of the malignant phenotype in prostate cancer, perhaps supporting cell growth or survival. FAS expression may be upregulat ed by alternate signaling pathways important for prostate cancer growth und er androgen withdrawal. The re-emergence of FAS expression and activity dur ing the development of androgen independence demonstrate that FAS may serve as a novel target for antimetabolite therapy in prostate cancer. Prostate 47:102-110, 2001. (C) 2001 Wiley-Liss, Inc.