Fatty Acid Synthase: A Metabolic Enzyme and Candidate Oncogene in Prostate Cancer
Fatty Acid Synthase: A Metabolic Enzyme and Candidate Oncogene in Prostate Cancer
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DOI：
10.1093/jnci/djp030
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发表时间：
2009-04-01
影响因子：
10.3
通讯作者：
Loda, Massimo
中科院分区：
文献类型：
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作者：
Migita, Toshiro;Ruiz, Stacey;Loda, Massimo
脂肪酸合成酶（FATCH）基因的过表达与前列腺癌的发生有关。我们试图直接评估FXR的致癌潜力。我们使用永生化的人前列腺上皮细胞（iPrEC）、雄激素受体过表达的iPrEC（AR-iPrEC）和稳定过表达FXR的人前列腺腺癌LNCaP细胞进行细胞增殖试验、软琼脂试验和免疫缺陷小鼠肿瘤形成试验。产生在前列腺中表达Festival的转基因小鼠以评估Festival对前列腺组织学的影响。通过Hoechst 33342染色和荧光激活细胞分选，在用内源性和外源性细胞凋亡途径刺激剂（即分别为喜树碱和抗Fas抗体）或靶向Fas的小干扰RNA（siRNA）处理的iPrEC-Fas细胞中评价细胞凋亡。通过使用最小二乘均值程序，在745例人前列腺癌样本中，将FXR表达与通过末端脱氧核苷酸转移酶介导的UTP末端标记方法评估的凋亡指数进行比较。在iPrEC、AR-iPrEC和LNCaP细胞中强制表达FcB可增加细胞增殖和软琼脂生长。同时表达FXR和雄激素受体（AR）的iPrEC在免疫缺陷小鼠中形成侵袭性腺癌（注射的14只小鼠中有12只形成肿瘤，而注射表达空载体的AR-iPrEC的14只小鼠中有0只形成肿瘤（P < .001，Fisher精确检验）;然而，仅表达FXR的iPrEC没有形成肿瘤。小鼠中的FIGHT 3转基因表达导致前列腺上皮内瘤形成，其发病率从8- 16周龄小鼠的10%增加到7个月或更大的小鼠的44%（P = 0.0028，Fisher精确检验），但在侵袭性肿瘤中没有。在LNCaP细胞中，siRNA介导的FcG沉默导致细胞凋亡。过表达Fas可保护iPrECs免于喜树碱诱导的凋亡，但不能保护iPrECs免于Fas受体诱导的凋亡。在人前列腺癌标本中，FXR表达与凋亡率呈负相关，（凋亡细胞的平均百分比，FcB表达的最低与最高四分位数：2.76 vs 1.34，差异= 1.41，95%置信区间= 0.45 - 2.39，这些观察结果表明，在AR的存在下，FXR可以作为前列腺癌癌基因，并且FXR通过抑制细胞凋亡的内在途径发挥其致癌作用。
Overexpression of the fatty acid synthase (FASN) gene has been implicated in prostate carcinogenesis. We sought to directly assess the oncogenic potential of FASN.We used immortalized human prostate epithelial cells (iPrECs), androgen receptor-overexpressing iPrECs (AR-iPrEC), and human prostate adenocarcinoma LNCaP cells that stably overexpressed FASN for cell proliferation assays, soft agar assays, and tests of tumor formation in immunodeficient mice. Transgenic mice expressing FASN in the prostate were generated to assess the effects of FASN on prostate histology. Apoptosis was evaluated by Hoechst 33342 staining and by fluorescence-activated cell sorting in iPrEC-FASN cells treated with stimulators of the intrinsic and extrinsic pathways of apoptosis (ie, camptothecin and anti-Fas antibody, respectively) or with a small interfering RNA (siRNA) targeting FASN. FASN expression was compared with the apoptotic index assessed by the terminal deoxynucleotidyltransferase-mediated UTP end-labeling method in 745 human prostate cancer samples by using the least squares means procedure. All statistical tests were two-sided.Forced expression of FASN in iPrECs, AR-iPrECs, and LNCaP cells increased cell proliferation and soft agar growth. iPrECs that expressed both FASN and androgen receptor (AR) formed invasive adenocarcinomas in immunodeficient mice (12 of 14 mice injected formed tumors vs 0 of 14 mice injected with AR-iPrEC expressing empty vector (P < .001, Fisher exact test); however, iPrECs that expressed only FASN did not. Transgenic expression of FASN in mice resulted in prostate intraepithelial neoplasia, the incidence of which increased from 10% in 8- to 16-week-old mice to 44% in mice aged 7 months or more (P = .0028, Fisher exact test), but not in invasive tumors. In LNCaP cells, siRNA-mediated silencing of FASN resulted in apoptosis. FASN overexpression protected iPrECs from apoptosis induced by camptothecin but did not protect iPrECs from Fas 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 of FASN expression: 2.76 vs 1.34, difference = 1.41, 95% confidence interval = 0.45 to 2.39, P-trend = .0046).These observations suggest that FASN can act as a prostate cancer oncogene in the presence of AR and that FASN exerts its oncogenic effect by inhibiting the intrinsic pathway of apoptosis.