Inhibition of tumor growth by a newly-identified activator for epidermal fatty acid binding protein (original) (raw)
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Long-chain fatty acid analogues suppress breast tumorigenesis and progression
Cancer research, 2014
Obesity and type 2 diabetes (T2D) are associated with increased breast cancer incidence and mortality, whereas carbohydrate-restricted ketogenic diets ameliorate T2D and suppress breast cancer. These observations suggest an inherent efficacy of nonesterified long-chain fatty acids (LCFA) in suppressing T2D and breast tumorigenesis. In this study, we investigated novel antidiabetic MEDICA analogues consisting of methyl-substituted LCFA that are neither β-oxidized nor esterified to generate lipids, prompting interest in their potential efficacy as antitumor agents in the context of breast cancer. In the MMTV-PyMT oncomouse model of breast cancer, in which we confirmed that tumor growth could be suppressed by a carbohydrate-restricted ketogenic diet, MEDICA treatment suppressed tumor growth, and lung metastasis, promoting a differentiated phenotype while suppressing mesenchymal markers. In human breast cancer cells, MEDICA treatment attenuated signaling through the STAT3 and c-Src tran...
Breast Cancer Research and Treatment, 2004
The lipogenic enzyme fatty acid synthase (FAS) is differentially overexpressed and hyperactivated in a biologically aggressive subset of breast carcinomas and minimally in most normal adult tissues, rendering it an interesting target for antineoplastic therapy development. Recently, a molecular connection between the HER-2/neu (c-erbB-2) oncogene and FAS has been described in human breast cancer cells . Here, we examined the relationship between breast cancer-associated FAS hyperactivity and HER-2/neu-induced breast cancer chemoresistance to taxanes. Co-administration of docetaxel (Taxotere ® ) and the mycotoxin cerulenin, a potent and non-competitive inhibitor of FAS activity, demonstrated strong synergism in HER-2/neu-overexpressing and docetaxel-resistant SK-Br3 cells, modest synergism in moderately HER-2/neu-expressing MCF-7 cells, and it showed additive effects in low HER-2/neu-expressing and docetaxel-sensitive MDA-MB-231 cells. Sequential exposure to cerulenin followed by docetaxel again yielded strong synergism in SK-Br3 cells, whereas antagonistic and moderate synergistic interactions were observed in MCF-7 and MDA-MB-231 cells, respectively. Importantly, inhibition of FAS activity dramatically decreased the expression of HER-2/neu oncogene in SK-Br3 breast cancer cells. To the best of our knowledge this is the first study demonstrating that FAS is playing an active role in HER-2/neu-induced breast cancer chemotherapy resistance.
Novel anti-fatty acid synthase compounds with anti-cancer activity in HER2+ breast cancer
Annals of the New York Academy of Sciences, 2010
Fatty acid synthase (FASN) expression and activity has emerged as a common phenotype in most human carcinomas, including breast cancer, and its expression is tightly linked to HER2 signaling pathways. The development of inhibitors of FASN activity has consequently appeared as a novel antitarget modality for treating cancer. However, the clinical use of FASN inhibitors, such as cerulenin, C75, and epigallocatechin 3-gallate (EGCG), is limited by anorexia and induced body weight loss or by its low in vivo potency and stability. Here, we summarize the design and development of G28UCM, the lead-compound of a novel family of synthetic FASN inhibitors, with both in vitro and in vivo activity in a human breast cancer model of FASN + and HER2 + .
2019
Recent advances in immunology and cancer research show that fatty acids, their metabolism and their sensing have a crucial role in the biology of many different cell types. Indeed, they are able to affect cellular behaviour with great implications for patho-physiology. Both the catabolic and anabolic pathways of fatty acids present us with a number of enzymes, receptors and ago-nists/antagonists that are potential therapeutic targets, some of which have already been successfully pursued. Fatty acids can affect the differentiation of immune cells, particularly T cells, as well as their activation and function, with important consequences for the balance between anti-and pro-inflammatory signals in immune diseases , such as rheumatoid arthritis, psoriasis, diabetes, obesity and cardiovascular conditions. In the context of cancer biology, fatty acids mainly provide substrates for energy production, which is of crucial importance to meet the energy demands of these highly proliferating cells. Fatty acids can also be involved in a broader transcrip-tional programme as they trigger signals necessary for tumorigenesis and can confer to cancer cells the ability to migrate and generate distant metastasis. For these reasons, the study of fatty acids represents a new research direction that can generate detailed insight and provide novel tools for the understanding of immune and cancer cell biology, and, more importantly, support the development of novel, efficient and fine-tuned clinical interventions. Here, we review the recent literature focusing on the involvement of fatty acids in the biology of immune cells, with emphasis on T cells, and cancer cells, from sensing and binding, to metabolism and downstream effects in cell signalling. Abbreviatons: ACC-acetyl-CoA carboxylase, ACLY-ATP citrate lyase, CPT-carnitine palmitoyl transferases, CRPC-castration-resistant prostate cancer, DHA-docosahexaenoic acid, EAE-experimental autoimmune encephalomyelitis, EMT-epithelial to mesenchymal transition, EPA-eicosapentaenoic acid, FABP-Fatty acid binding protein, FADS-fatty acyl-CoA desaturase, FAS-fatty acid synthase, GA-gastric adenocarcinoma, HCC-hepatocellular carcinoma, HDAC-histone deacetylase, HFD-high fat diet, ILC-innate lymphoid cell, LAL-lysosomal acid lipase, LMW-E-low molecular weight isoform of cyclin E, LPS-lipopolysaccharide, mCRPC-metastatic CRCP, NK-natural killer, PI(4,5)P2-phosphatidylinositol (4,5) bisphosphate, PLD-phospholipase D, PPAR-peroxisome proliferator-activated receptor, PUFA-polyunsaturated fatty acid, SCD-stearoyl-CoA desaturase, SREBP-sterol regulatory element binding protein, Tconv-conventional T cell, TCR-T cell receptor, Teff-T effector cell, Th-T helper cell, Tm-T memory cell, TNBC-triple-negative breast cancer, Treg-regulatory T cell, wt-wild type.
Fatty acid synthase regulates estrogen receptor-α signaling in breast cancer cells
Oncogenesis
Fatty acid synthase (FASN), the key enzyme for endogenous synthesis of fatty acids, is overexpressed and hyperactivated in a biologically aggressive subset of sex steroid-related tumors, including breast carcinomas. Using pharmacological and genetic approaches, we assessed the molecular relationship between FASN signaling and estrogen receptor alpha (ERα) signaling in breast cancer. The small compound C75, a synthetic slow-binding inhibitor of FASN activity, induced a dramatic augmentation of estradiol (E 2)-stimulated, ERα-driven transcription. FASN and ERα were both necessary for the synergistic activation of ERα transcriptional activity that occurred following co-exposure to C75 and E 2 : first, knockdown of FASN expression using RNAi (RNA interference) drastically lowered (4100 fold) the amount of E 2 required for optimal activation of ERα-mediated transcriptional activity; second, FASN blockade synergistically increased E 2-stimulated ERα-mediated transcriptional activity in ERα-negative breast cancer cells stably transfected with ERα, but not in ERα-negative parental cells. Non-genomic, E 2-regulated cross-talk between the ERα and MAPK pathways participated in these phenomena. Thus, treatment with the pure antiestrogen ICI 182 780 or the potent and specific inhibitor of MEK/ERK, U0126, was sufficient to abolish the synergistic nature of the interaction between FASN blockade and E 2-stimulated ERα transactivation. FASN inhibition suppressed E 2-stimulated breast cancer cell proliferation and anchorageindependent colony formation while promoting the reduction of ERα protein. FASN blockade resulted in the increased expression and nuclear accumulation of the cyclin-dependent kinase inhibitors p21 WAF1/CIP1 and p27 Kip1 , two critical mediators of the therapeutic effects of antiestrogen in breast cancer, while inactivating AKT, a key mediator of E 2-promoted anchorage-independent growth. The ability of FASN to regulate E 2 /ERα signaling may represent a promising strategy for anticancer treatment involving a new generation of FASN inhibitors.
A new class of human fatty acid synthase inhibitors: Synthesis and their anticancer evaluation
2018
thiadiazoles have been designed, synthesized and screened for their in vitro antitumour activity against breast cancer cell lines. Three compounds namely, 3pentadecyl-6-phenyl[1,2,4]triazolo[3,4-b][1,3,4]thiadiazole (6e), 3-heptadecyl-6-phenyl[1,2,4]triazolo[3,4-b][1,3,4]thiadiazole (6j) and 3-heptadecyl-6(3-nitrophenyl)[1,2,4]triazolo[3,4b][1,3,4]-thiadiazole (6g) have displayed comparable activities towards human breast cancer lines. Molecular docking studies have been carried out on the crystal structure of human fatty acid synthase thioesterase domain (2PX6) by using GLIDE integrated Maestro 9.3 version. The designed compounds have shown good binding interactions with the active site residues present in the enzyme and have given very good G-scores when compared to the known inhibitor orlistat.
New Synthetic Inhibitors of Fatty Acid Synthase with Anticancer Activity
Journal of Medicinal Chemistry, 2012
Fatty acid synthase (FASN) is a lipogenic enzyme that is highly expressed in different human cancers. Here we report the development of a new series of polyphenolic compounds 5−30 that have been evaluated for their cytotoxic capacity in SK-Br3 cells, a human breast cancer cell line with high FASN expression. The compounds with an IC 50 < 50 μM have been tested for their ability to inhibit FASN activity. Among them, derivative 30 blocks the 90% of FASN activity at low concentration (4 μM), is highly cytotoxic in a broad panel of tumor cells, induces apoptosis, and blocks the activation of HER2, AKT, and ERK pathways. Remarkably, 30 does not activate carnitine palmitoyltransferase-1 (CPT-1) nor induces in mice weight loss, which are the main drawbacks of other previously described FASN inhibitors. Thus, FASN inhibitor 30 may aid the validation of this enzyme as a therapeutic target for the treatment of cancer.
Role of macrophage lipids in regulating tumoricidal activity
Cellular Immunology, 1983
Peritoneal macrophages (Mb) from mice became cytotoxic after incubation with lymphokine (LK); tumoricidal activity was evident with Mg treated with LK for 4 hr, became maximal after 8-12 hr of incubation, and decreased to control levels by 24-36 hr. LK induced marked changes in M@ lipid composition: cellular content of cholesterol (CHOL) and polyunsaturated fatty acid (UFA) content of cellular lipids (especially 18:3) increased two-to threefold aher 8 hr when the cells showed maximal tumoricidal activity. Cellular lipid and fatty-acid content returned to control levels by 24 hr when the M&J had lost tumoricidal activity. These changes were not observed with equal numbers of Mg cultured in control supematants. To analyze the role of CHOL and UFA in Mb tumor cytotoxicity, casein-induced peritoneal M+ were enriched in CHOL or linolenic acid (18:3) and then tested for their ability to kill 1023 tumor cells. The 18:3-enriched cells were markedly tumoricidal, whereas controls cultured in delipidized medium alone or enriched with saturated fatty acid (18:O) were not cytotoxic. CHOL-enriched Mb were not tumoricidal; indeed, these cells were inhibited in their killing after treatment with LK compared to M& cultured in delipidized medium with LK alone. The effects of 18:3 and CHOL enrichment of the M&I on their metabolic status, inflammatory function, and tumor cell-binding capacity were tested. The 18:3-enriched Mg were depressed in their ability to synthesize protein and in phagocytic activity compared to controls; these cells showed a transient increase in superoxide release. MI#J cultured with 18:3 for 48 hr were also cytotoxic for P8 I5 tumor cells, but did not show an enhanced capacity for P8 15 binding compared to controls. CHOL-enriched Mg were similar to control cells in their protein synthesizing and phagocytic activities; these cells also showed an early transient increase in superoxide release. CHOL-enriched M4 were not cytotoxic for P8 I5 cells, but bound the tumor cells more readily than did the 18:3-enriched M&J. The data suggest that endogenous levels of 18:3 and CHOL can regulate Mb tumor cytotoxicity, but not through regulation of Mb protein synthesis, oxidative metabolism, or augmented capacity for tumor target binding.