Fatty acid synthase is a prognostic marker and associated with immune infiltrating in gastric cancers precision medicine

Aim: Fatty acid synthase (FASN), a key enzyme for de novo synthesis of fatty acids, has been identified as an oncogene in some tumor types; however, the function of FASN in gastric cancer (GC) is poorly elucidated. Method: Integrative bioinformatics analyses were performed to unveil the role of FASN in tumor progression and cancer-associated immunology of GC. Result: FASN was overexpressed in the GC tissues and correlated with an inferior survival outcome, and largely contributed to the carcinogenesis of GC. Moreover, FASN expression was closely associated with the immune-infiltrating levels of CD8+ T, CD4+ T, neutrophils, macrophages and dendritic cells. Conclusion: FASN was closely associated with GC and may be involved in the tumorigenesis and cancer–immune interactions, and could be a promising prognostic and therapeutic biomarker in GC.

Download Full-text

Satisfying the fatty acid demand of prostate cancer: De novo synthesis versus uptake as alternative and potentially cooperative prostate cancer phenotypes.

Journal of Clinical Oncology ◽

10.1200/jco.2017.35.6_suppl.107 ◽

2017 ◽

Vol 35 (6_suppl) ◽

pp. 107-107

Author(s):

Sandra Marlene Gaston ◽

James Kearns ◽

George W. Adams ◽

Soroush Rais-Bahrami ◽

Jeffrey Nix ◽

...

Keyword(s):

Prostate Cancer ◽

Fatty Acid ◽

Fatty Acid Synthase ◽

De Novo ◽

Selective Advantage ◽

Low Grade ◽

De Novo Synthesis ◽

Fatty Acid Binding ◽

Variable Expression ◽

Gleason Pattern

107 Background: Malignant transformation increases cellular demand for fatty acids (FA). Many cancers show increased expression of fatty acid synthase (FASN); FASN catalyzes the de novo synthesis of the FA palmitate. While research has focused on FASN and de novo tumor FA synthesis, observations suggest that alternate mechanisms for FA acquisition are also important, including studies showing that cancer cells can be rescued from FASN inhibition by exogenous palmitate. Using a biopsy-based approach, we identified a PrCa subtype with outlier (>10 fold) overexpression of fatty acid binding protein 5 (FABP5). FABP5 facilitates the utilization of palmitate and other FAs from outside the cell; a FABP5 overexpression phenotype may confer a selective advantage when dietary FAs are abundant or when FASN is targeted as a therapy. Methods: 244 prostate biopsy patients were prospectively enrolled. Tissue prints were collected from each core for RNA and DNA preparation. mRNA was analyzed using Affymetrix arrays and TaqMan qrtPCR assays. Immunohistochemistry (IHC) was performed using archival radical prostatectomy (RP) specimens. Results: mRNA analyses revealed a PrCa subtype with >10 x overexpression of FABP; this phenotype was observed in 7% of 268 cores with Gleason sum (GS) 7-10 PrCa. We also observed a second subtype with >10 x overexpression of FASN in 9% of GS 7-10 cores. With few exceptions these two PrCa subtypes showed an “either-or” pattern with top-quartile overexpression of FABP5 or FASN but not both (Spearman r = - 0.385; P < 0.0001). IHC confirmed variable expression, including “patchwork” PrCas with high Gleason pattern (GP) areas overexpressing FABP5 next to low GP areas overexpressing FASN. The net result may be a selective advantage for the high grade cancer if FABP5 allows it to exploit the FA being synthesized by the adjacent low grade focus Conclusions: Identification of a PrCa subtype with high levels of FABP5 overexpression suggests a previously unrecognized mechanism by which some PrCas can increase FA supply without de novo synthesis; such a PrCa subtype might be particularly sensitive to dietary interventions and relatively insensitive to FASN inhibitors.

Download Full-text

Synthesis of new C75 derivatives, Fatty Acid Synthase inhibitors with cytotoxic properties

Bionatura ◽

10.21931/rb/cs/2019.02.01.9 ◽

2019 ◽

Vol 02 (Bionatura Conference Serie) ◽

Cited By ~ 1

Author(s):

Kamil Makowski ◽

Javier Ariza ◽

Jordi Garcia ◽

Laura Herrero ◽

Marta López ◽

...

Keyword(s):

Fatty Acid ◽

Fatty Acid Synthase ◽

De Novo ◽

Human Cancer ◽

Acid Synthesis ◽

The Other ◽

Aliphatic Chain ◽

Key Enzyme ◽

Cancer Tissues ◽

Derivatives Of

The fatty-acid synthase (FAS) is the key enzyme that executes de novo fatty acid synthesis and is overexpressed in some human cancer tissues. C75 is a synthetic FAS inhibitor, which produces the death of cancer cells. In this work, we synthesized three derivatives of C75, two homologs with 1 and 2 carbons more in the beta position of the lactone and the other one with a change in the elongation of the aliphatic chain in gamma position from 8 to 15 carbons. The results from FAS inhibition and cytotoxic properties suggest that the performed changes in the derivatives decrease their activity.

Download Full-text

Acetyl-CoA mediated autoacetylation of fatty acid synthase in de novo lipogenesis

10.1101/2022.01.06.475252 ◽

2022 ◽

Author(s):

Ting Miao ◽

Jinoh Kim ◽

Ping Kang ◽

Hua Bai

Keyword(s):

Fatty Acid ◽

Fatty Acid Synthase ◽

De Novo ◽

Regulatory System ◽

De Novo Lipogenesis ◽

Lysine Acetylation ◽

Dependent Manner ◽

Acetyl Coa ◽

Lipogenic Genes

De novo lipogenesis (DNL) is a highly regulated metabolic process, which is known to be activated through transcriptional regulation of lipogenic genes, including fatty acid synthase (FASN). Unexpectedly, we find that the expression of FASN protein remains unchanged during Drosophila larval development when lipogenesis is hyperactive. Instead, acetylation modification of FASN is highly upregulated in fast-growing larvae. We further show that lysine K813 is highly acetylated in developing larvae, and its acetylation is required for upregulated FASN activity, body fat accumulation, and normal development. Intriguingly, K813 is rapidly autoacetylated by acetyl-CoA in a dosage-dependent manner, independent of known acetyltransferases. Furthermore, the autoacetylation of K813 is mediated by a conserved P-loop-like motif (N-xx-G-x-A). In summary, this work uncovers a novel role of acetyl-CoA-mediated autoacetylation of FASN in developmental lipogenesis and reveals a self-regulatory system that controls metabolic homeostasis by linking acetyl-CoA, lysine acetylation, and DNL.

Download Full-text

Antiangiogenics and Hypoxic Response: Role of Fatty Acid Synthase Inhibitors

Current Drug Targets ◽

10.2174/1389450117666160502151857 ◽

2016 ◽

Vol 17 (15) ◽

pp. 1735-1746 ◽

Cited By ~ 3

Author(s):

Maria Jose Bueno ◽

Jesus Sanchez ◽

Ramon Colomer ◽

Miguel Quintela-Fandino

Keyword(s):

Fatty Acid ◽

Fatty Acid Synthase ◽

Hypoxic Response

Download Full-text

In vivo study of the biosynthesis of long-chain fatty acids using deuterated water

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.1995.269.2.e247 ◽

1995 ◽

Vol 269 (2) ◽

pp. E247-E252 ◽

Cited By ~ 6

Author(s):

H. O. Ajie ◽

M. J. Connor ◽

W. N. Lee ◽

S. Bassilian ◽

E. A. Bergner ◽

...

Keyword(s):

Fatty Acids ◽

Fatty Acid ◽

De Novo ◽

Chain Elongation ◽

Deuterated Water ◽

De Novo Synthesis ◽

Isotopomer Distribution ◽

Long Chain ◽

Mass Isotopomer

To determine the contributions of preexisting fatty acid, de novo synthesis, and chain elongation in long-chain fatty acid (LCFA) synthesis, the synthesis of LCFAs, palmitate (16:0), stearate (18:0), arachidate (20:0), behenate (22:0), and lignocerate (24:0), in the epidermis, liver, and spinal cord was determined using deuterated water and mass isotopomer distribution analysis in hairless mice and Sprague-Dawley rats. Animals were given 4% deuterated water for 5 days or 8 wk in their drinking water. Blood was withdrawn at the end of these times for the determination of deuterium enrichment, and the animals were killed to isolate the various tissues for lipid extraction for the determination of the mass isotopomer distributions. The mass isotopomer distributions in LCFA were incompatible with synthesis from a single pool of primer. The synthesis of palmitate, stearate, arachidate, behenate, and lignocerate followed the expected biochemical pathways for the synthesis of LCFAs. On average, three deuterium atoms were incorporated for every addition of an acetyl unit. The isotopomer distribution resulting from chain elongation and de novo synthesis can be described by the linear combination of two binomial distributions. The proportions of preexisting, chain elongation, and de novo-synthesized fatty acids as a percentage of the total fatty acids were determined using multiple linear regression analysis. Fractional synthesis was found to vary, depending on the tissue type and the fatty acid, from 47 to 87%. A substantial fraction (24-40%) of the newly synthesized molecules was derived from chain elongation of unlabeled (recycled) palmitate.

Download Full-text

LncRNA CRNDE attenuates chemoresistance in gastric cancer via SRSF6-regulated alternative splicing of PICALM

Molecular Cancer ◽

10.1186/s12943-020-01299-y ◽

2021 ◽

Vol 20 (1) ◽

Author(s):

Feifei Zhang ◽

Hui Wang ◽

Jiang Yu ◽

Xueqing Yao ◽

Shibin Yang ◽

...

Keyword(s):

Gastric Cancer ◽

Alternative Splicing ◽

Noncoding Rna ◽

De Novo ◽

Acquired Resistance ◽

Genetic Alterations ◽

Clinical Samples ◽

Autophagy Flux ◽

Resistance To Chemotherapy

AbstractDe novo and acquired resistance, which are mainly mediated by genetic alterations, are barriers to effective routine chemotherapy. However, the mechanisms underlying gastric cancer (GC) resistance to chemotherapy are still unclear. We showed that the long noncoding RNA CRNDE was related to the chemosensitivity of GC in clinical samples and a PDX model. CRNDE was decreased and inhibited autophagy flux in chemoresistant GC cells. CRNDE directly bound to splicing protein SRSF6 to reduce its protein stability and thus regulate alternative splicing (AS) events. We determined that SRSF6 regulated the PICALM exon 14 skip splice variant and triggered a significant S-to-L isoform switch, which contributed to the expression of the long isoform of PICALM (encoding PICALML). Collectively, our findings reveal the key role of CRNDE in autophagy regulation, highlighting the significance of CRNDE as a potential prognostic marker and therapeutic target against chemoresistance in GC.

Download Full-text

Role of the enoyl reductase domain in the regulation of fatty acid synthase activity by interdomain interaction.

Journal of Biological Chemistry ◽

10.1016/s0021-9258(19)68854-x ◽

1981 ◽

Vol 256 (16) ◽

pp. 8379-8383

Author(s):

A.J. Poulose ◽

P.E. Kolattukudy

Keyword(s):

Fatty Acid ◽

Fatty Acid Synthase ◽

Enoyl Reductase ◽

Interdomain Interaction ◽

Reductase Domain

Download Full-text

The composition and metabolism of fatty acids in Ips paraconfusus Lanier (Coleoptera: Scolytidae)

Canadian Journal of Zoology ◽

10.1139/z72-171 ◽

1972 ◽

Vol 50 (10) ◽

pp. 1263-1267 ◽

Cited By ~ 4

Author(s):

K. R. Penner ◽

J. S. Barlow

Keyword(s):

Fatty Acids ◽

Fatty Acid Composition ◽

Fatty Acid ◽

Sexual Dimorphism ◽

Acid Composition ◽

De Novo ◽

Monounsaturated Fatty Acids ◽

Ips Paraconfusus ◽

Chain Elongation ◽

De Novo Synthesis

The fatty acid composition of newly emerged Ips paraconfusus Lanier shows no sexual dimorphism and is approximately as follows: C14:0, 0.5%; C16:0, 23.0%; C16:1, 6%; C18:0, 3%; C18:1, 55%; C18:2, 9%; C18:3, 2%. Both sexes, but particularly the female, use up fatty acids, particularly the monounsaturated acids, during reproduction. Isotope from 1-14C-acetate injected into newly emerged females appeared in all saturated and monounsaturated fatty acids within 30 min. There was evidence of de novo synthesis of C14:0 and C16:0, chain elongation of C16:0 to C18:0, and desaturation of C16:0 and C18:0 to yield C16:1 and C18:1 respectively.

Download Full-text