單酰甘油脂肪酶調(diào)節(jié)促進(jìn)癌癥發(fā)病的一課件

1、單酰甘油脂肪酶調(diào)節(jié)促進(jìn)癌癥發(fā)病的一個脂肪酸網(wǎng)絡(luò)Monoacylglycerol Lipase Regulates a Fatty Acid Network that Promotes Cancer PathogenesisDaniel K. Nomura, Jonathan Z. Long, Sherry Niessen, Heather S. Hoover, Shu-Wing Ng and Benjamin F. Cravatt, 來自：斯克里普斯研究所 The Scripps Research Institute 崔艷娥 20092513410 Monoacylglycerol lipas

2、e (MAGL) is elevated in aggressive human cancer cells Loss of MAGL lowers fatty acid levels in cancer cells and impairs pathogenicity MAGL controls a signaling network enriched in protumorigenic lipids A high-fat diet can restore the growth of tumors lacking MAGL in vivo人類癌細(xì)胞中單酰甘油脂肪酶的含量提高癌細(xì)胞中減少的MAGL

3、會降低脂肪酸的量以及減少致病性MAGL調(diào)節(jié)促進(jìn)癌癥發(fā)病的一個脂肪酸網(wǎng)絡(luò)Tumor cells display progressive changes in metabolism that correlate with malignancy, including development of a lipogenic phenotype. How stored fats are liberated and remodeled to support cancer pathogenesis, however, remains unknown. Here, we show that the enzyme

4、 monoacylglycerol lipase (MAGL) is highly expressed in aggressive human cancer cells and primary tumors, where it regulates a fatty acid network enriched in oncogenic signaling lipids that promotes migration, invasion, survival, and in vivo tumor growth. Overexpression of MAGL in nonaggressive cance

5、r cells recapitulates this fatty acid network and increases their pathogenicityphenotypes that are reversed by an MAGL inhibitor. Impairments in MAGL-dependent tumor growth are rescued by a high-fat diet, indicating that exogenous sources of fatty acids can contribute to malignancy in cancers lackin

6、g MAGL activity. Together, these findings reveal how cancer cells can co-opt a lipolytic enzyme to translate their lipogenic state into an array of protumorigenic signals腫瘤細(xì)胞展示了在新陳代謝中的與惡性腫瘤相關(guān)的進(jìn)展，包括脂肪性表型，儲存的脂肪細(xì)胞擺脫束縛以及被改造后促進(jìn)癌癥的發(fā)病機(jī)理，然而，仍未知。這里，單酰甘油脂肪酶在人癌癥細(xì)胞中和初級的腫瘤細(xì)胞中是高度表達(dá)的，調(diào)節(jié)促進(jìn)癌癥發(fā)病的一個脂肪酸網(wǎng)絡(luò)，促進(jìn)移動，入侵，存活，以及

7、在活的生物體內(nèi)增長。在無攻擊性的癌細(xì)胞中超表達(dá)的單酰甘油脂肪酶概括了這個脂肪酸網(wǎng)路增加了他們的致病性表型的轉(zhuǎn)變，致病性表型本是被單酰甘油脂肪酶的抑制劑抑制的，高脂肪的飲食緩解了單酰甘油脂肪酶在依賴的腫瘤細(xì)胞中的損傷，表明外源脂肪酸有助于缺乏單酰甘油脂肪酶活性的癌細(xì)胞的惡化，同時，這些發(fā)現(xiàn)顯示癌細(xì)胞能指派分解脂肪的酶轉(zhuǎn)化他們的脂肪生成的物質(zhì)成為大量的致癌信號。RESULTDisruption of MAGL Expression and Activity Impairs Cancer PathogenicityMAGL Overexpression Increases FFAs and the

8、Aggressiveness of Cancer CellsMetabolic Rescue of Impaired Pathogenicity in MAGL-Disrupted Cancer CellsMAGL Regulates a Fatty Acid Network Enrichedin Protumorigenic SignalsActivity-Based Proteomic Analysis of HydrolyticEnzymes in Human Cancer CellsMAGL Regulates Free Fatty Acid Levels in Aggressive

9、Cancer Cells單酰甘油脂肪酶的表達(dá)和活性的破壞減少了癌細(xì)胞的致病性單酰甘油脂肪酶的超表達(dá)增加了游離脂肪酸和攻擊性癌細(xì)胞單酰甘油脂肪酶調(diào)節(jié)脂肪酸網(wǎng)絡(luò)加強(qiáng)致癌信號在攻擊性癌細(xì)胞中單酰甘油脂肪酶調(diào)控游離脂肪酸Figure 3. High-Grade Primary Human Ovarian Tumors PossessElevated MAGL Activity and FFAs Compared to Benign Tumors(A) C20:4 MAG hydrolytic activity measurements for individual tumor specimens.Pr

10、etreatment with JZL184 (1 mM, 30 min) confirmed that the majorityof the observed hydrolytic activity is due to MAGL.(B) Summary graph of MAGL activity in benign versus high-grade tumors,where each value is expressed as the JZL184-sensitive portion of totalC20:4 MAG hydrolytic activity shown in part

11、(A).(C) Levels of FFAs in benign versus high-grade tumors. *p 0.01 for highgradeversus benign tumor groups. Data are presented as means SEM;n = 1013/group. MAGL活動和FFAs升高相比在良性腫瘤中(A)C20:4 MAG個別的腫瘤標(biāo)本水解活性測量。JZL184預(yù)處理(1毫米,30分鐘)證實多數(shù)所觀察到的水解活性是由于MAGL。(B)總結(jié)MAGL活動圖良高惡性腫瘤,每一個值表示JZL184敏感部分在C20:4總的水解活動中（圖A）顯示的一部

12、分。(C)FFAs的水平在良高惡性腫瘤中。* * p 0.01為惡性與良性腫瘤組。給出了數(shù)據(jù)SEM;n = 13 /組。our results indicate that MAGL serves as key metabolic hub in aggressive cancer cells, where the enzyme regulates a fatty acid network that feeds into a number of protumorigenic signaling pathways. Additional studies will be required to det

13、ermine precisely how FFAs are converted to protumorigenic lipid transmitters, although some obvious candidate pathways can be schematized . It will be interesting to determine whether any of the enzymatic components of these pathways are also dysregulated in pathogenic cancers. One might also antici

14、pate that cancer cells could exhibit heightened levels of additional hydrolytic activities (e.g., di- and tri-acylglycerol hydrolysis) to further capitalize on their lipogenic state, although we should note that the aggressive cancer cells examined herein displayed much lower di- and tri-acylglycero

15、l lipase activity compared to MAGL activity, and these former activities did not differ between aggressive and nonaggressive cancer cells . Finally, considering that endocannabinoids (Wang etal., 2008), -oxidation (Buzzai etal., 2005,Liu, 2006), and fatty acid-sustained glycolysis (Przybytkowski eta

16、l., 2007) have each been described as potential contributing elements to tumorigenesis, it is possible that these pathways may proverelevant for MAGL-dependent aggressiveness in other types of cancer. Independent of which of these mechanisms isoperational in specific cancers, our data suggest that they would each function downstream of MAGL, thus designating this enzyme as a potentially exciting pharmacological target for future cancer therapy 研究表明單酰甘油脂肪酶被看做是攻擊性癌細(xì)胞的新陳代謝中心的關(guān)鍵，在那里酶調(diào)控脂肪酸網(wǎng)絡(luò)流入大量致癌信號傳導(dǎo)通路。進(jìn)一步的研究將被要求來精確確定游離脂肪酸如何被轉(zhuǎn)換成致癌脂質(zhì)信號傳送器,雖然一些明顯的候選途徑可以被系統(tǒng)化。它將會是有趣的去確定的,是否這些途徑的任何的酶的組成部分也特異表達(dá)，我