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脂肪酸合酶:前列腺癌中的一种代谢酶和候选癌基因
Fatty Acid Synthase: A Metabolic Enzyme and Candidate Oncogene in Prostate Cancer

Background: Overexpression of the fatty acid synthase (FASN) genehas been implicated in prostate carcinogenesis. We sought todirectly assess the oncogenic potential of FASN.

Methods: We used immortalized human prostate epithelial cells(iPrECs), androgen receptor–overexpressing iPrECs (AR-iPrEC), andhuman prostate adenocarcinoma LNCaP cells that stably overexpressedFASN for cell proliferation assays, soft agar assays, and tests oftumor formation in immunodeficient mice. Transgenic mice expressingFASN in the prostate were generated to assess the effects of FASNon prostate histology. Apoptosis was evaluated by Hoechst 33342staining and by fluorescence-activated cell sorting in iPrEC-FASNcells treated with stimulators of the intrinsic and extrinsicpathways of apoptosis (ie, camptothecin and anti-Fas antibody,respectively) or with a small interfering RNA (siRNA) targetingFASN. FASN expression was compared with the apoptotic indexassessed by the terminal deoxynucleotidyltransferase-mediated UTPend-labeling method in 745 human prostate cancer samples by usingthe least squares means procedure. All statistical tests weretwo-sided.

Results: Forced expression of FASN in iPrECs, AR-iPrECs, and LNCaPcells increased cell proliferation and soft agar growth. iPrECsthat expressed both FASN and androgen receptor (AR) formed invasiveadenocarcinomas in immunodeficient mice (12 of 14 mice injectedformed tumors vs 0 of 14 mice injected with AR-iPrEC expressingempty vector (P < .001, Fisher exact test); however, iPrECs thatexpressed only FASN did not. Transgenic expression of FASN in miceresulted in prostate intraepithelial neoplasia, the incidence ofwhich increased from 10% in 8- to 16-week-old mice to 44% in miceaged 7 months or more (P = .0028, Fisher exact test), but not ininvasive tumors. In LNCaP cells, siRNA-mediated silencing of FASNresulted in apoptosis. FASN overexpression protected iPrECs fromapoptosis induced by camptothecin but did not protect iPrECs fromFas receptor–induced apoptosis. In human prostate cancer specimens,FASN expression was inversely associated with the apoptotic rate(mean percentage of apoptotic cells, lowest vs highest quartile ofFASN expression: 2.76 vs 1.34, difference = 1.41, 95% confidenceinterval = 0.45 to 2.39, Ptrend = .0046).

Conclusions: These observations suggest that FASN can act as aprostate cancer oncogene in the presence of AR and that FASN exertsits oncogenic effect by inhibiting the intrinsic pathway ofapoptosis.

http://jnci.oxfordjournals.org/cgi/content/abstract/101/7/519

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