Increased fatty acid synthase as a therapeutic target in androgen-independent prostate cancer progression.
BACKGROUND
Fatty acid synthase (FAS) performs the anabolic conversion of dietary carbohydrate or protein to fat. FAS expression is low in most normal tissues, but is elevated in many human cancers, including androgen-sensitive 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 expression and activity under androgenic and androgen-depleted conditions, and were tested for sensitivity to antimetabolite drugs that target fatty acid synthesis.


RESULTS
While FAS expression in the prostate was androgen responsive, it persisted or was reactivated in human prostate carcinoma after androgen ablation, and was high in 82% of lethal tumors examined at autopsy. Similar patterns 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 cancer 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 upregulated by alternate signaling pathways important for prostate cancer growth under androgen withdrawal. The re-emergence of FAS expression and activity during the development of androgen independence demonstrate that FAS may serve as a novel target for antimetabolite therapy in prostate cancer.
Pizer
E S
ES
Department of Pathology, The Johns Hopkins University School of Medicine, Baltimore, Maryland, USA. epizer@jhmi.edu
Pflug
B R
BR
Bova
G S
GS
Han
W F
WF
Udan
M S
MS
Nelson
J B
JB
D015107:4-Butyrolactone / Q000031:analogs & derivatives* / Q000494:pharmacology; D000728:Androgens / Q000502:physiology*; D000818:Animals; D000911:Antibodies, Monoclonal; D000970:Antineoplastic Agents / Q000494:pharmacology; D015153:Blotting, Western; D002855:Chromatography, Thin Layer; D004791:Enzyme Inhibitors / Q000494:pharmacology; D064429:Fatty Acid Synthases / Q000037:antagonists & inhibitors / Q000096:biosynthesis*; D006801:Humans; D007150:Immunohistochemistry; D008055:Lipids / Q000032:analysis; D008297:Male; D051379:Mice; D008819:Mice, Nude; D009376:Neoplasms, Hormone-Dependent / Q000201:enzymology; D011471:Prostatic Neoplasms / Q000201:enzymology*; D011897:Random Allocation; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
C406734:4-methylene-2-octyl-5-oxofuran-3-carboxylic acid; D000728:Androgens; D000911:Antibodies, Monoclonal; D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D008055:Lipids; D064429:Fatty Acid Synthases; D015107:4-Butyrolactone