单酰甘油脂肪酶调节促进癌症发病的一课件

1、单酰甘油脂肪酶调节促进癌症发病的一个脂肪酸网络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, 来自：斯克里普斯研究所 The Scripps Research Institute 崔艳娥 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人类癌细胞中单酰甘油脂肪酶的含量提高癌细胞中减少的MAGL

3、会降低脂肪酸的量以及减少致病性MAGL调节促进癌症发病的一个脂肪酸网络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肿瘤细胞展示了在新陈代谢中的与恶性肿瘤相关的进展，包括脂肪性表型，储存的脂肪细胞摆脱束缚以及被改造后促进癌症的发病机理，然而，仍未知。这里，单酰甘油脂肪酶在人癌症细胞中和初级的肿瘤细胞中是高度表达的，调节促进癌症发病的一个脂肪酸网络，促进移动，入侵，存活，以及

7、在活的生物体内增长。在无攻击性的癌细胞中超表达的单酰甘油脂肪酶概括了这个脂肪酸网路增加了他们的致病性表型的转变，致病性表型本是被单酰甘油脂肪酶的抑制剂抑制的，高脂肪的饮食缓解了单酰甘油脂肪酶在依赖的肿瘤细胞中的损伤，表明外源脂肪酸有助于缺乏单酰甘油脂肪酶活性的癌细胞的恶化，同时，这些发现显示癌细胞能指派分解脂肪的酶转化他们的脂肪生成的物质成为大量的致癌信号。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单酰甘油脂肪酶的表达和活性的破坏减少了癌细胞的致病性单酰甘油脂肪酶的超表达增加了游离脂肪酸和攻击性癌细胞单酰甘油脂肪酶调节脂肪酸网络加强致癌信号在攻击性癌细胞中单酰甘油脂肪酶调控游离脂肪酸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活动和FFAs升高相比在良性肿瘤中(A)C20:4 MAG个别的肿瘤标本水解活性测量。JZL184预处理(1毫米,30分钟)证实多数所观察到的水解活性是由于MAGL。(B)总结MAGL活动图良高恶性肿瘤,每一个值表示JZL184敏感部分在C20:4总的水解活动中（图A）显示的一部

12、分。(C)FFAs的水平在良高恶性肿瘤中。* * p 0.01为恶性与良性肿瘤组。给出了数据SEM;n = 13 /组。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 研究表明单酰甘油脂肪酶被看做是攻击性癌细胞的新陈代谢中心的关键，在那里酶调控脂肪酸网络流入大量致癌信号传导通路。进一步的研究将被要求来精确确定游离脂肪酸如何被转换成致癌脂质信号传送器,虽然一些明显的候选途径可以被系统化。它将会是有趣的去确定的,是否这些途径的任何的酶的组成部分也特异表达，我