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Fasn inhibitors

Li Yang, Fuquan Zhang, Xin Wang, Ying Tsai, Kuang-Hsiang Chuang, Peter C Keng, Soo Ok Lee, Yuhchyau Chen
Cisplatin-resistant A549CisR and H157CisR cell lines were developed by treating parental A549 (A549P) and H157 (H157P) cells. These cisplatin-resistant cells showed slight growth retardation, but exhibited higher epithelial-mesenchymal transition (EMT) and increased metastatic potential compared to parental cells. We observed a highly up-regulated fatty acid synthase (FASN) level in A549CisR and H157CisR cells compared to parental cells and the up-regulation of FASN was also detected in A549P and H157P cells after short time treatment with cisplatin, suggesting that the high level of FASN in cisplatin-resistant cells may be from the accumulated cellular responses during cisplatin-resistance developmental process...
July 25, 2016: Oncotarget
Da Zhou, Bing-Hang Li, Jing Wang, Yong-Nian Ding, Yan Dong, Yuan-Wen Chen, Jian-Gao Fan
BACKGROUND: Prolyl oligopeptidase (POP) is a serine endopeptidase that is widely distributed in vivo, particularly in the liver. Significant changes in functional mitochondrial proteins involved with mitochondrial oxidoreductases/transporters and nucleic acid binding proteins were observed after POP inhibition in the liver, which suggested a role of POP in regulating liver energy metabolism. Steatosis in nonalcoholic fatty liver disease (NAFLD) is associated with disturbances in lipid and energy metabolism in hepatocytes...
2016: PloS One
Huai-Peng Lin, Zhou-Li Cheng, Ruo-Yu He, Lei Song, Meng-Xin Tian, Lisha Zhou, Beezly S Groh, Weiren Liu, Min-Biao Ji, Chen Ding, Ying-Hong Shi, Kun-Liang Guan, Dan Ye, Yue Xiong
Fatty acid synthase (FASN) is the terminal enzyme in de novo lipogenesis and plays a key role in cell proliferation. Pharmacological inhibitors of FASN are being evaluated in clinical trials for treatment of cancer, obesity and other diseases. Here we report a previously unknown mechanism of FASN regulation involving its acetylation by KAT8 and its deacetylation by HDAC3. FASN acetylation promoted its degradation via the ubiquitin-proteasome pathway. FASN acetylation enhanced its association with the E3 ubiquitin-ligase TRIM21...
October 10, 2016: Cancer Research
Bruna Corominas-Faja, Luciano Vellon, Elisabet Cuyàs, Maria Buxó, Begoña Martin-Castillo, Dolors Serra, Jordi García, Javier A Menendez, Ruth Lupu
Fatty acid synthase (FASN) is a key lipogenic enzyme for de novo fatty acid biosynthesis and a druggable metabolic oncoprotein that is activated in most human cancers. We evaluated whether the HER2-driven lipogenic phenotype might represent a biomarker for sensitivity to pharmacological FASN blockade. A majority of clinically HER2-positive tumors were scored as FASN overexpressors in a series of almost 200 patients with invasive breast carcinoma. Re-classification of HER2-positive breast tumors based on FASN gene expression predicted a significantly inferior relapse-free and distant metastasis-free survival in HER2+/FASN+ patients...
October 7, 2016: Histology and Histopathology
Thelma S Angeles, Robert L Hudkins
Elevated lipogenesis has been associated with a variety of diseases including obesity, cancer and nonalcoholic fatty liver disease (NAFLD). Fatty acid synthase (FASN) plays a pivotal role in de novo lipogenesis, making this multi-catalytic protein an attractive target for therapeutic intervention. Recently, the first FASN inhibitor successfully advanced through the drug development process and entered clinical evaluation in oncology. Areas covered: This review discusses the biological roles of FASN in three prominent disease areas: cancer, obesity-related disorders and non-alcoholic fatty liver disease...
October 5, 2016: Expert Opinion on Drug Discovery
Sadat A Aziz, Luisa A Wakeling, Satomi Miwa, Goiuri Alberdi, John E Hesketh, Dianne Ford
Promoting the development of brown or beige adipose tissue may protect against obesity and related metabolic features, and potentially underlies protective effects of genistein in mice. We observed that application of genistein to 3T3-L1 adipocytes changed the lipid distribution from large droplets to a multilocular distribution, reduced mRNAs indicative of white adipocytes (ACC, Fasn, Fabp4, HSL, chemerin and resistin) and increased mRNAs that are a characteristic feature of brown/beige adipocytes (CD-137 and UCP1)...
September 27, 2016: Molecular Nutrition & Food Research
G Li, M Li, J Hu, R Lei, H Xiong, H Ji, H Yin, Q Wei, G Hu
Reprogrammed metabolism is one of the hallmarks of cancer. The dysregulation of glycolysis in cancer has been heavily studied. However, it remains largely unclear how other metabolic processes are regulated in cancer cells. Here we show that microRNA-182 (miR-182) suppresses pyruvate dehydrogenase (PDH) kinase 4 (PDK4) and promotes lung tumorigenesis. miR-182 is dysregulated and inversely correlated with PDK4 in human lung adenocarcinomas. The miR-182-PDK4 axis regulates lung cancer cell growth by modulating the activity of PDH, the gatekeeping enzyme of pyruvate flux into acetyl-CoA, and subsequently de novo lipogenesis of cancer cells...
September 19, 2016: Oncogene
Maosong Ye, Xia Gu, Yang Han, Meiling Jin, Tao Ren
BACKGROUND: Lung cancer is the leading cause of cancer-related death worldwide. Patients with lung cancer are very frequently present with pulmonary infections, in particular with Gram-negative bacteria. Herein, we investigated the effect of the co-presence of Gram-negative bacteria on outgrowth and metastasis of lung cancer cells in clinical patients. METHODS: Lung cancer cells were isolated from clinical surgical tissues. Heat-inactivated E. coli was used as Gram-negative bacteria...
August 2016: Journal of Thoracic Disease
Arun John, Vetrivel Umashankar, A Samdani, Manoharan Sangeetha, Subramanian Krishnakumar, Perinkulam Ravi Deepa
Fatty acid synthase (FASN, UniProt ID: P49327) is a multienzyme dimer complex that plays a critical role in lipogenesis. Consequently, this lipogenic enzyme has gained tremendous biomedical importance. The role of FASN and its inhibition is being extensively researched in several clinical conditions, such as cancers, obesity, and diabetes. X-ray crystallographic structures of some of its domains, such as β-ketoacyl synthase, acetyl transacylase, malonyl transacylase, enoyl reductase, β-ketoacyl reductase, and thioesterase, (TE) are already reported...
2016: Bioinformatics and Biology Insights
A Maleah Holland, Michael D Roberts, Petey W Mumford, Christopher Brooks Mobley, Wesley C Kephart, Christine F Conover, Luke A Beggs, Alexander Balaez, Dana M Otzel, Joshua F Yarrow, Stephen E Borst, Darren T Beck
The influence of the aromatase enzyme on the chronic fat-sparing effects of testosterone requires further elucidation. Our purpose was to determine whether chronic anastrozole (AN; aromatase inhibitor) treatment alters testosterone-mediated lipolytic/lipogenic gene expression in visceral fat. 10 month old F344 rats (n=6/group) received SHAM surgery, orchiectomy(ORX), ORX+testosterone-enanthate(TEST; 7.0mg/week), or ORX+TEST+AN(0.5mg/day), with drug treatment beginning 14 days post-surgery. At day 42, ORX animals exhibited nearly undetectable serum testosterone and 29% higher retroperitoneal fat mass versus SHAM (p<0...
August 18, 2016: Journal of Applied Physiology
Sarah Crunkhorn
No abstract text is available yet for this article.
July 29, 2016: Nature Reviews. Drug Discovery
Gang Zhao, Lei Dong, Haitao Shi, Hong Li, Xiaolan Lu, Xiaoyan Guo, Jinhai Wang
Fatty acid synthase (FASN) has emerged as a unique oncologic target for the treatment of cancers, including hepatocellular carcinoma (HCC). However, effective inhibitors of FASN for cancer treatment are lacking. MicroRNAs (miRNAs) have emerged as novel and endogenic inhibitors of gene expression. In the present study, we aimed to investigate the role of miR‑1207‑5p in HCC and the regulation of FASN through miR‑1207‑5p. The expression of miR-1207-5p was markedly reduced in HCC tissues and cell lines as detected with real‑time quantitative polymerase chain reaction (qPCR)...
September 2016: Oncology Reports
Jinfeng Wu, Juan Du, Xiuqiong Fu, Bin Liu, Huihui Cao, Ting Li, Tao Su, Jinhua Xu, Anfernee Kai-Wing Tse, Zhi-Ling Yu
Icaritin (IT) is a flavonoid isolated from Herba Epimedii. In this study, we evaluated the anti-melanoma activities of IT, and determined its cytotoxic mechanism. We found that IT exerted cytotoxicity to melanoma cells. Furthermore, IT induced melanoma cell apoptosis, which was accompanied with PARP cleavage. Mechanistically, IT suppressed p-STAT3 (tyr705) level in parallel with increases of p-STAT3 (ser727), p-ERK and p-AKT. IT significantly inhibited STAT3 nuclear translocation and reduced the levels of STAT3 -targeted genes...
June 13, 2016: Oncotarget
Yazan Alwarawrah, Philip Hughes, David Loiselle, David A Carlson, David B Darr, Jamie L Jordan, Jessie Xiong, Lucas M Hunter, Laura G Dubois, J Will Thompson, Manjusha M Kulkarni, Annette N Ratcliff, Jesse J Kwiek, Timothy A J Haystead
Many tumors are dependent on de novo fatty acid synthesis to maintain cell growth. Fatty acid synthase (FASN) catalyzes the final synthetic step of this pathway, and its upregulation is correlated with tumor aggressiveness. The consequences and adaptive responses of acute or chronic inhibition of essential enzymes such as FASN are not fully understood. Herein we identify Fasnall, a thiophenopyrimidine selectively targeting FASN through its co-factor binding sites. Global lipidomics studies with Fasnall showed profound changes in cellular lipid profiles, sharply increasing ceramides, diacylglycerols, and unsaturated fatty acids as well as increasing exogenous palmitate uptake that is deviated more into neutral lipid formation rather than phospholipids...
June 23, 2016: Cell Chemical Biology
Arun John, Umashankar Vetrivel, Krishnakumar Subramanian, Perinkulam Ravi Deepa
Human fatty acid synthase (hFASN), a homo dimeric lipogenic enzyme with seven catalytic domains, is an important clinical target in cancer, metabolic syndrome and infections. Here, molecular modeling and docking methods were implemented to examine the inter-molecular interactions of thioesterase (TE) domain in hFASN with its physiological substrate, and to identify potential chemical inhibitors. TE catalyses the hydrolysis of thioester bond between palmitate and the 4´ phosphopantetheine of acyl carrier protein, releasing 16-carbon palmitate...
May 4, 2016: Journal of Biomolecular Structure & Dynamics
Masashi Inafuku, Kensaku Takara, Naoyuki Taira, Ruwani N Nugara, Yasuo Kamiyama, Hirosuke Oku
BACKGROUND: The leaves of Cirsium brevicaule A. GRAY (CL) significantly decreased hepatic lipid accumulation and the expression of fatty acid synthase gene (FASN) in mice. PURPOSE: We aimed to purify and identify the active compound(s) from CL and determine the inhibitory mechanism of expression of FASN. METHODS: We purified monogalactosyldiacylglycerol (MGDG) from extracts of CL (CL-MGDG) and showed that it was the active CL component through analyses of its effects on the expression of genes of human breast cancer cell line, SKBR-3...
May 15, 2016: Phytomedicine: International Journal of Phytotherapy and Phytopharmacology
Cunzhen Zhao, Xiaochang Chen, Wenjing Wu, Wusu Wang, Weijun Pang, Gongshe Yang
Intramuscular fat (IMF) has been demonstrated as one of the crucial factors of livestock meat quality. The MAT2B protein with MAT2α catalyzes the formation of methyl donor S- adenosylmethionine (SAMe) to mediate cell metabolism including proliferation and apoptosis. However, the regulatory effect of MAT2B on IMF deposition is still unclear. In this study, the effect of MAT2B on adipogenesis and its potential mechanism during porcine intramuscular preadipocyte differentiation was studied. The results showed that overexpression of MAT2B promoted adipogenesis and significantly up-regulated the mRNA and protein levels of adipogenic marker genes including FASN, PPARγ and aP2, consistently, knockdown of MAT2B inhibited lipid accumulation and down-regulated the mRNA and protein levels of the above genes...
May 15, 2016: Experimental Cell Research
Lan Zhou, Sufang Jiang, Qiang Fu, Kelly Smith, Kailing Tu, Hua Li, Yuhua Zhao
Both fatty acid synthase (FASN) and ErbB2 have been shown to promote breast cancer cell migration. However, the underlying molecular mechanism remains poorly understood and there is no reported evidence that directly links glycolysis to breast cancer cell migration. In this study, we investigated the role of FASN, ErbB2-mediated glycolysis in breast cancer cell migration. First, we compared lactate dehydrogenase A (LDHA) protein levels, glycolysis and cell migration between FASN, ErbB2-overexpressing SK-BR-3 cells and FASN, ErbB2-low-expressing MCF7 cells...
May 2016: Oncology Reports
Barrie Peck, Almut Schulze
Metabolic reprogramming is a central feature of transformed cells. Cancer metabolism is now fully back in the focus of cancer research, as the interactions between oncogenic signalling and cellular metabolic processes are uncovered. One aspect of metabolic reprogramming in cancer is alterations in lipid metabolism. In contrast to most untransformed tissues, which satisfy their demand from dietary lipids, cancer cells frequently re-activate de novo lipogenesis. However, compounds targeting fatty acid synthase (FASN), a multiprotein complex integral to lipogenesis, have so far shown limited efficacy in pre-clinical cancer models and to date only one FASN inhibitor has entered clinical trials...
August 2016: FEBS Journal
Tanner K Hill, Amanda L Davis, Frances B Wheeler, Sneha S Kelkar, Erica C Freund, W Todd Lowther, Steven J Kridel, Aaron M Mohs
Fatty acid synthase (FASN), the enzyme that catalyzes de novo synthesis of fatty acids, is expressed in many cancer types. Its potential as a therapeutic target is well recognized, but inhibitors of FASN have not yet been approved for cancer therapy. Orlistat (ORL), an FDA-approved lipase inhibitor, is also an effective inhibitor of FASN. However, ORL is extremely hydrophobic and has low systemic uptake after oral administration. Thus, new strategies are required to formulate ORL for cancer treatment as a FASN inhibitor...
March 7, 2016: Molecular Pharmaceutics
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