Pflug Beth R, Pecher Stefana M, Brink Alisa W, Nelson Joel B, Foster Barbara A
University of Pittsburgh, Department of Urology, Pittsburgh, Pennsylvania 15232, USA.
Prostate. 2003 Nov 1;57(3):245-54. doi: 10.1002/pros.10297.
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.
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.
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.
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.
脂肪酸合酶（FAS）是将碳水化合物转化为脂肪酸所需的主要酶。最近的证据表明，FAS活性对前列腺癌的生长和存活至关重要，因为阻断该酶的活性会导致细胞死亡。在本研究中，研究了FAS上调在小鼠前列腺转基因腺癌（TRAMP）模型前列腺肿瘤进展过程中的作用。还分析了TRAMP前列腺肿瘤细胞和组织对FAS抗代谢物的敏感性，以确定FAS抑制在前列腺癌治疗中的治疗潜力。
通过对TRAMP组织（包括不同年龄小鼠的原发性和转移性病变）进行免疫组织化学评估FAS表达。使用源自TRAMP的细胞系在体外和在TRAMP组织中体内研究FAS途径活性。通过FAS抗代谢物抑制14C-乙酸转化为脂肪酸、细胞生长抑制和凋亡分析，确定TRAMP细胞系和组织对靶向FAS的抗代谢药物（2R，3S）-2,3-环氧-4-氧代-7,10-反式，反式十二碳二烯酰胺（浅蓝菌素）和C-75的敏感性。
与非转基因同窝小鼠相比，TRAMP小鼠前列腺中FAS的高表达和活性在12周龄时明显，并且随着年龄、肿瘤进展和转移病变而进一步增加。在这些模型中，FAS途径抑制导致细胞存活率呈剂量依赖性降低和酶活性降低。
这些数据表明，FAS表达的上调在TRAMP模型中前列腺肿瘤发生中起作用，因此可为人类前列腺癌提供有价值的见解。鉴于肿瘤细胞对FAS抗代谢物的反应，FAS可能成为前列腺癌治疗的新靶点。
