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Jingqian Guan Xizi Jiang Junda Gai Xiaodan Sun Jinming Zhao Ji Li Yizhuo Li Ming Cheng Tengjiao Du Lin Fu Qingchang Li 《Journal of cellular and molecular medicine》2020,24(23):14039
Sirtuin 5 (SIRT5) is a NAD+‐dependent class III protein deacetylase, and its role in prostate cancer has not yet been reported. Therefore, to explore the diagnosis and treatment of prostate cancer, we investigated the effect of SIRT5 on prostate cancer. Sirtuin 5 was assessed by immunohistochemistry in 57 normal and cancerous prostate tissues. We found that the tissue expression levels of SIRT5 in patients with Gleason scores ≥7 were significantly different from those in patients with Gleason scores <7 (P < .05, R > 0). Further, mass spectrometry and pathway screening experiments showed that SIRT5 regulated the activity of the mitogen‐activated protein kinase (MAPK) pathway, which in turn modulated the expression of MMP9 and cyclin D1. Being a substrate of SIRT5, acetyl‐CoA acetyltransferase 1 (ACAT1) was regulated by SIRT5. SIRT5 also regulated MAPK pathway activity through ACAT1. These results revealed that SIRT5 promoted the activity of the MAPK pathway through ACAT1, increasing the ability of prostate cancer cells to proliferate, migrate and invade. Overall, these results indicate that SIRT5 expression is closely associated with prostate cancer progression. Understanding the underlying mechanism may provide new targets and methods for the diagnosis and treatment of the disease. 相似文献
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《Cell cycle (Georgetown, Tex.)》2013,12(21):3956-3963
We have previously suggested that ketone body metabolism is critical for tumor progression and metastasis. Here, using a co-culture system employing human breast cancer cells (MCF7) and hTERT-immortalized fibroblasts, we provide new evidence to directly support this hypothesis. More specifically, we show that the enzymes required for ketone body production are highly upregulated within cancer-associated fibroblasts. This appears to be mechanistically controlled by the stromal expression of caveolin-1 (Cav-1) and/or serum starvation. In addition, treatment with ketone bodies (such as 3-hydroxy-butyrate, and/or butanediol) is sufficient to drive mitochondrial biogenesis in human breast cancer cells. This observation was also validated by unbiased proteomic analysis. Interestingly, an MCT1 inhibitor was sufficient to block the onset of mitochondrial biogenesis in human breast cancer cells, suggesting a possible avenue for anticancer therapy. Finally, using human breast cancer tumor samples, we directly confirmed that the enzymes associated with ketone body production (HMGCS2, HMGCL and BDH1) were preferentially expressed in the tumor stroma. Conversely, enzymes associated with ketone re-utilization (ACAT1) and mitochondrial biogenesis (HSP60) were selectively associated with the epithelial tumor cell compartment. Our current findings are consistent with the “two-compartment tumor metabolism” model. Furthermore, they suggest that we should target ketone body metabolism as a new area for drug discovery, for the prevention and treatment of human cancers. 相似文献
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Previous studies have shown that acyl-coenzyme A:cholesterol acyl transferase (ACAT), an enzyme that controls cellular equilibrium between free cholesterol and cholesteryl esters, modulates proteolytic processing of APP in cell-based and animal models of Alzheimer's disease. Here we report that ACAT-1 RNAi reduced cellular ACAT-1 protein by approximately 50% and cholesteryl ester levels by 22% while causing a slight increase in the free cholesterol content of ER membranes. This correlated with reduced proteolytic processing of APP and 40% decrease in Abeta secretion. These data show that even a modest decrease in ACAT activity can have robust suppressive effects on Abeta generation. 相似文献
4.
In this study, via a bioactivity-guided fractionation of MeOH extracts of the fruits of Piper nigrum, alkamide (5) and five previously-identified alkamides were isolated. Their structures were elucidated via spectroscopic analysis ((1)H, (13)C NMR and ESI-MS), as follows: retrofractamide A (1), pipercide (2), piperchabamide D (3), pellitorin (4), dehydroretrofractamide C (5) and dehydropipernonaline (6). The IC(50) values determined for the compounds were 24.5 (1), 3.7 (2), 13.5 (3), 40.5 (4), 60 (5) and 90 microM (6), according to the results of an ACAT enzyme assay system using rat liver microsomes. These compounds all inhibited cholesterol esterification in HepG2 cells. 相似文献
5.
Li YANG Jiang CHEN Catherine C. Y. CHANG Xin-Ying YANG Zhen-Zhen WANG Ta-Yuan CHANG and Bo-Liang LI* State Key Laboratory of Molecular Biology Institute of Biochemistry Cell Biology Shanghai Institutes for Biological Sciences the Chinese Academy of Sciences Shanghai China Department of Biochemistry Dartmouth Medical School Hanover NH USA 《Acta biochimica et biophysica Sinica》2004,(4)
Acyl-coenzyme A:cholesterol acyltransferase (ACAT)is an integral membrane protein, which is mainly locatedin rough endoplasmic reticulum (ER), and is responsiblefor catalyzing the intracellular formation of cholesterylester from cholesterol and long-chain fatty acyl-coenzymeA [1,2]. Human ACAT1 cDNA K1 was firstly cloned andfunctionally expressed in 1993 [3]. Further studies withspecific anti-ACAT1 antibody (DM10) illustrated that onemajor 50 kD ACAT1 protein was expressed in various… 相似文献
6.
操作含长插入片段的DNA克隆时 ,经常需要进行亚克隆和测序实验。通常的方法首先是得到插入片段的限制性内切酶谱 ,然后选择合适的内切酶消化DNA ,分离靶片段 ,将其连接入质粒载体中进行下一步操作。但这种方法工作量大 ,步骤繁琐。在此 ,介绍一种不需要做限制性内切酶谱分析 ,而根据靶片段的旁侧序列直接进行亚克隆实验的方法。首先 ,选择合适的限制性内切酶消化含长插入片段的DNA克隆 ,其中一种酶切在已知的旁侧序列上 ,另一为随机选择 ;然后酶切混合物与线性化的质粒载体连接 ,转化细菌得到一“亚克隆库” ;将其中的克隆挑选入 96孔板培养后 ,按行或列混合菌液得到相应的“pool” ;最后 ,用PCR方法筛选获得含靶DNA片段的阳性克隆 ,其中所用的引物一个与已知的旁侧DNA序列配对 ,另一个与质粒载体上序列配对 ,PCR扩增已知的旁侧DNA片段以鉴定阳性克隆。多次独立实验表明该方法简单有效 ,可广泛用于亚克隆和DNA步移实验 相似文献
7.
Kimiyuki Shibuya Katsumi Kawamine Toru Miura Chiyoka Ozaki Toshiyuki Edano Ken Mizuno Yasunobu Yoshinaka Yoshihiko Tsunenari 《Bioorganic & medicinal chemistry》2018,26(14):4001-4013
We describe our molecular design of aortic-selective acyl-coenzyme A:cholesterol O-acyltransferase (ACAT, also abbreviated as SOAT) inhibitors, their structure–activity relationships (SARs) and their pharmacokinetic (PK) and pharmacological profiles. The connection of two weak ligands—N-(2,6-diisopropylphenyl)acetamide (50% inhibitory concentration [IC50]?=?8.6?μM) and 2-(methylthio)benzo[d]oxazole (IC50?=?31?μM)—via a linker comprising a 6 methylene group chains yielded a highly potent molecule, 9-(benzo[d]oxazol-2-ylthio)-N-(2,6-diisopropylphenyl)nonanamide (3h) that exhibited high potency (IC50?=?0.004?μM) toward aortic ACAT. This head-to-tail design made it possible to markedly enhance the activity to 2150- to 7750-fold and to discriminate the isoform-selectivity based on the double-induced fit mechanism. At doses of 1 and 3?mg/kg, 3h significantly decreased the lipid-accumulation areas in the aortic arch to 74 and 69%, respectively without reducing the plasma total cholesterol level in high fat- and cholesterol-fed F1B hamsters. Here, we demonstrate the antiatherosclerotic effect of 3hin vivo via its direct action on aortic ACAT and its powerful modulator of cholesterol level. This molecule is a potential therapeutic agent for the treatment of diseases involving ACAT-1 overexpression. 相似文献
8.
Lipid droplets (LDs) are ubiquitous cellular organelles for lipid storage which are composed of a neutral lipid core bounded by a protein decorated phospholipid monolayer. Although lipid storage is their most obvious function, LDs are far from inert as they participate in maintaining lipid homeostasis through lipid synthesis, metabolism, and transportation. Furthermore, they are involved in cell signaling and other molecular events closely associated with human disease such as dyslipidemia, obesity, lipodystrophy, diabetes, fatty liver, atherosclerosis, and others. The last decade has seen a great increase in the attention paid to LD biology. Regardless, many fundamental features of LD biology remain obscure. In this review, we will discuss key aspects of LD biology including their biogenesis, growth and regression. We will also summarize the current knowledge about the role LDs play in human disease, especially from the perspective of the dynamics of the associated proteins. This article is part of a Special issue entitled Cardiac adaptations to obesity, diabetes and insulin resistance, edited by Professors Jan F.C. Glatz, Jason R.B. Dyck and Christine Des Rosiers. 相似文献
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10.
Markku Lehto Vesa M Olkkonen 《Biochimica et Biophysica Acta (BBA)/Molecular and Cell Biology of Lipids》2003,1631(1):1-11
Proteins/genes showing high sequence homology to the mammalian oxysterol binding protein (OSBP) have been identified in a variety of eukaryotic organisms from yeast to man. The unifying feature of the gene products denoted as OSBP-related proteins (ORPs) is the presence of an OSBP-type ligand binding (LB) domain. The LB domains of OSBP and its closest homologue bind oxysterols, while data on certain other family members suggest interaction with phospholipids. Many ORPs also have a pleckstrin homology (PH) domain in the amino-terminal region. The PH domains of the family members studied in detail are known to interact with membrane phosphoinositides and play an important role in the intracellular targeting of the proteins. It is plausible that the ORPs constitute a regulatory apparatus that senses the status of specific lipid ligands in membranes, using the PH and/or LB domains, and mediates information to yet poorly known downstream machineries. Functional studies carried out on the ORP proteins in different organisms indicate roles of the gene family in diverse cellular processes including control of lipid metabolism, regulation of vesicle transport, and cell signalling events. 相似文献