Increased fatty acid synthase expression and activity during progression of prostate cancer in the TRAMP model.
BACKGROUND
Fatty acid synthase (FAS) is the major enzyme required to convert carbohydrates to fatty acids. Recent evidence suggests that FAS activity is essential for prostate cancer growth and survival, since blocking the enzyme activity results in cell death. In this study, the role of FAS up-regulation during prostate tumor progression in the transgenic adenocarcinoma of mouse prostate (TRAMP) model was investigated. Sensitivity to FAS anti-metabolites was also analyzed in TRAMP prostate tumor cells and tissue to determine therapeutic potential of FAS inhibition in the treatment of prostate cancer.


METHODS
FAS expression was evaluated by immunohistochemistry of TRAMP tissues, including primary and metastatic lesions in mice of varying ages. FAS pathway activity was studied in vitro using TRAMP-derived cell lines and in vivo in TRAMP tissues. The sensitivity of TRAMP cell lines and tissues to the antimetabolite drugs (2R,3S)-2,3-epoxy-4-oxo-7,10-trans, transdodecadienamide (cerulenin) and C-75, which target FAS, was determined by FAS antimetabolite inhibition of 14C-acetate conversion to fatty acids, cell growth inhibition, and apoptosis analyses.


RESULTS
High FAS expression and activity in the TRAMP mouse prostate was evident at 12 weeks of age compared with nontransgenic littermates and further increased with age, tumor progression, and in metastatic lesions. FAS pathway inhibition resulted in a dose-dependent reduction in cell survival and decreased enzyme activity in these models.


CONCLUSIONS
These data suggest that the up-regulation of FAS expression play a role in tumorigenesis of the prostate in the TRAMP model and hence can provide valuable insight into human prostate cancer. Given the response of tumor cells to FAS antimetabolites, FAS may serve as a novel target for prostate cancer therapy.
D000230:Adenocarcinoma / Q000201:enzymology* / Q000473:pathology; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D002569:Cerulenin / Q000494:pharmacology; D004195:Disease Models, Animal; D018450:Disease Progression; D004791:Enzyme Inhibitors / Q000494:pharmacology; D064429:Fatty Acid Synthases / Q000037:antagonists & inhibitors / Q000096:biosynthesis* / Q000378:metabolism; D007150:Immunohistochemistry; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D011471:Prostatic Neoplasms / Q000201:enzymology* / Q000473:pathology
D004791:Enzyme Inhibitors; D002569:Cerulenin; D064429:Fatty Acid Synthases