Expression of Fatty Acid Synthase Depends on NAC1 and Is Associated with Recurrent Ovarian Serous Carcinomas.
Expression of Fatty Acid Synthase Depends on NAC1 and Is Associated with Recurrent Ovarian Serous Carcinomas.
复制标题
DOI：
10.1155/2010/285191
复制
发表时间：
2010
影响因子：
--
通讯作者：
Shih IeM
中科院分区：
文献类型：
--
作者：
Ueda SM;Yap KL;Davidson B;Tian Y;Murthy V;Wang TL;Visvanathan K;Kuhajda FP;Bristow RE;Zhang H;Shih IeM
我们之前的报告表明，NAC1是一种含BTB/POZ结构域的核蛋白，在复发性卵巢浆液性癌中表达上调，并参与癌细胞耐药性的产生。本研究应用定量蛋白质组学，通过比较表达显性负性NAC1构建体N130和不表达该构建体的SKOV3细胞的蛋白质组，来鉴定受NAC1调控的蛋白质。从被N130下调（即被NAC1上调）的蛋白质中，我们选择进一步对脂肪酸合酶（FASN）进行特性分析。与蛋白质水平的变化相似，SKOV3细胞中的FASN转录水平因N130诱导或NAC1敲低而显著降低。免疫组织化学显示，卵巢浆液性癌组织中NAC1和FASN的免疫强度具有高度显著的相关性（P <.0001）。此外，我们发现复发性浆液性癌比其匹配的原发肿瘤表现出更高的FASN免疫强度（P <.001）。多变量分析显示，浆液性癌中FASN染色评分>1与更差的总生存时间相关（P <.01）。最后，一种新的FASN抑制剂C93在卡铂/紫杉醇耐药的卵巢癌细胞中诱导了大量凋亡。总之，我们表明NAC1对卵巢浆液性癌中FASN的表达至关重要，并且FASN的表达与肿瘤复发和疾病侵袭性显著相关。耐药肿瘤细胞对FASN的依赖性表明，基于FASN的疗法对复发性卵巢癌患者具有潜在的应用价值。
Our previous reports demonstrated that NAC1, a BTB/POZ domain-containing nuclear protein, upregulates in recurrent ovarian serous carcinoma and participates in developing drug resistance in cancer cells. The current study applies quantitative proteomics to identify the proteins controlled by NAC1 by comparing the proteomes of SKOV3 cells with and without expression of a dominant negative NAC1 construct, N130. From the proteins that are downregulated by N130 (upregulated by NAC1), we chose to further characterize fatty acid synthase (FASN). Similar to change in protein level, the FASN transcript level in SKOV3 cells was significantly reduced by N130 induction or by NAC1 knockdown. Immunohistochemistry showed that NAC1 and FASN immunointensities in ovarian serous carcinoma tissues had a highly significant correlation (P < .0001). Moreover, we found that recurrent serous carcinomas exhibited higher FASN immunointensities than their matched primary tumors (P < .001). Multivariate analysis showed that an FASN staining score of >1 in serous carcinomas was associated with a worse overall survival time (P < .01). Finally, C93, a new FASN inhibitor, induced massive apoptosis in carboplatin/paclitaxel resistant ovarian cancer cells. In conclusion, we show that NAC1 is essential for FASN expression in ovarian serous carcinomas and the expression of FASN significantly correlates with tumor recurrence and disease aggressiveness. The dependence of drug resistant tumor cells on FASN suggests a potential application of FASN-based therapeutics for recurrent ovarian cancer patients.
登录
查看更多内容
影响因子：
7.3
作者：
JENSEN, V;LADEKARL, M;SOERENSEN, FB
通讯作者：
SOERENSEN, FB
DOI：
10.1038/labinvest.2008.97
发表时间：
2008-12
期刊：
Laboratory investigation; a journal of technical methods and pathology
影响因子：
--
作者：
通讯作者：
--
影响因子：
4.2
作者：
Korutla, Laxminarayana;Wang, Peijie;Mackler, Scott A.
通讯作者：
Mackler, Scott A.
影响因子：
13.8
作者：
Kuhajda, FP;Landree, LE;Ronnett, GV
通讯作者：
Ronnett, GV
影响因子：
11.5
作者：
Gupta, Divya;Venkatesh, Madhukumar;Mani, Sridhar
通讯作者：
Mani, Sridhar