Molecule Information

General Information of the Molecule (ID: Mol04001)
Name
Fatty acid synthase (FASN) ,Rattus norvegicus
Synonyms
Type I FAS
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Molecule Type
Protein
Gene Name
Fasn
Gene ID
50671
Sequence
MEEVVIAGMSGKLPESENLQEFWANLIGGVDMVTDDDRRWKAGLYGLPKRSGKLKDLSKF
DASFFGVHPKQAHTMDPQLRLLLEVSYEAIVDGGINPASLRGTNTGVWVGVSGSEASEAL
SRDPETLLGYSMVGCQRAMMANRLSFFFDFKGPSIALDTACSSSLLALQNAYQAIRSGEC
PAAIVGGINLLLKPNTSVQFMKLGMLSPDGTCRSFDDSGNGYCRAEAVVAVLLTKKSLAR
RVYATILNAGTNTDGCKEQGVTFPSGEAQEQLIRSLYQPGGVAPESLEYIEAHGTGTKVG
DPQELNGITRSLCAFRQSPLLIGSTKSNMGHPEPASGLAALTKVLLSLENGVWAPNLHFH
NPNPEIPALLDGRLQVVDRPLPVRGGIVGINSFGFGGANVHVILQPNTQQAPAPAPHAAL
PHLLHASGRTMEAVQGLLEQGRQHSQDLAFVSMLNDIAATPTAAMPFRGYTVLGVEGHVQ
EVQQVPASQRPLWFICSGMGTQWRGMGLSLMRLDSFRESILRSDEALKPLGVKVSDLLLS
TDEHTFDDIVHSFVSLTAIQIALIDLLTSMGLKPDGIIGHSLGEVACGYADGCLSQREAV
LAAYWRGQCIKDANLPAGSMAAVGLSWEECKQRCPPGVVPACHNSEDTVTISGPQAAVNE
FVEQLKQEGVFAKEVRTGGLAFHSYFMEGIAPTLLQALKKVIREPRPRSARWLSTSIPEA
QWQSSLARTSSAEYNVNNLVSPVLFQEALWHVPEHAVVLEIAPHALLQAVLKRGVKPSCT
IIPLMKRDHKDNLEFFLTNLGKVHLTGIDINPNALFPPVEFPVPRGTPLISPHIKWDHSQ
TWDIPVAEDFPNGSSSSSATVYNIDASSESSDHYLVDHCIDGRVLFPGTGYLYLVWKTLA
RSLSLSLEETPVVFENVTFHQATILPRTGTVPLEVRLLEASHAFEVSDSGNLIVSGKVYQ
WEDPDSKLFDHPEVPIPAESESVSRLTQGEVYKELRLRGYDYGPHFQGVYEATLEGEQGK
LLWKDNWVTFMDTMLQISILGFSKQSLQLPTRVTAIYIDPATHLQKVYMLEGDTQVADVT
TSRCLGVTVSGGVYISRLQTTATSRRQQEQLVPTLEKFVFTPHVEPECLSESAILQKELQ
LCKGLAKALQTKATQQGLKMTVPGLEDLPQHGLPRLLAAACQLQLNGNLQLELGEVLARE
RLLLPEDPLISGLLNSQALKACIDTALENLSTLKMKVVEVLAGEGHLYSHISALLNTQPM
LQLEYTATDRHPQALKDVQTKLQQHDVAQGQWDPSGPAPTNLGALDLVVCNCALATLGDP
ALALDNMVAALKDGGFLLMHTVLKGHALGETLACLPSEVQPGPSFLSQEEWESLFSRKAL
HLVGLKKSFYGTALFLCRRLSPQDKPIFLPVEDTSFQWVDSLKSILATSSSQPVWLTAMN
CPTSGVVGLVNCLRKEPGGHRIRCILLSNLSSTSHVPKLDPGSSELQKVLESDLVMNVYR
DGAWGAFRHFQLEQDKPEEQTAHAFVNVLTRGDLASIRWVSSPLKHMQPPSSSGAQLCTV
YYASLNFRDIMLATGKLSPDAIPGKWASRDCMLGMEFSGRDKCGRRVMGLVPAEGLATSV
LLSPDFLWDVPSSWTLEEAASVPVVYTTAYYSLVVRGRIQHGETVLIHSGSGGVGQAAIS
IALSLGCRVFTTVGSAEKRAYLQARFPQLDDTSFANSRDTSFEQHVLLHTGGKGVDLVLN
SLAEEKLQASVRCLAQHGRFLEIGKFDLSNNHPLGMAIFLKNVTFHGILLDALFEGANDS
WREVAELLKAGIRDGVVKPLKCTVFPKAQVEDAFRYMAQGKHIGKVLVQVREEEPEAMLP
GAQPTLISAISKTFCPEHKSYIITGGLGGFGLELARWLVLRGAQRLVLTSRSGIRTGYQA
KHVREWRRQGIHVLVSTSNVSSLEGARALIAEATKLGPVGGVFNLAMVLRDAMLENQTPE
LFQDVNKPKYNGTLNLDRATREACPELDYFVAFSSVSCGRGNAGQSNYGFANSTMERICE
QRRHDGLPGLAVQWGAIGDVGIILEAMGTNDTVVGGTLPQRISSCMEVLDLFLNQPHAVL
SSFVLAEKKAVAHGDGEAQRDLVKAVAHILGIRDLAGINLDSSLADLGLDSLMGVEVRQI
LEREHDLVLPIREVRQLTLRKLQEMSSKAGSDTELAAPKSKNDTSLKQAQLNLSILLVNP
EGPTLTRLNSVQSSERPLFLVHPIEGSITVFHSLAAKLSVPTYGLQCTQAAPLDSIPNLA
AYYIDCIKQVQPEGPYRVAGYSFGACVAFEMCSQLQAQQGPAPAHNNLFLFDGSHTYVLA
YTQSYRAKLTPGCEAEAEAEAICFFIKQFVDAEHSKVLEALLPLKSLEDRVAAAVDLITR
SHQSLDRRDLSFAAVSFYYKLRAADQYKPKAKYHGNVILLRAKTGGTYGEDLGADYNLSQ
VCDGKVSVHIIEGDHRTLLEGRGLESIINIIHSSLAEPRVSVREG
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3D-structure
PDB ID
2PNG
Classification
Transferase
Method
Solution nmr
Resolution
No Resolution Dat Å
Function
Fatty acid synthetase is a multifunctional enzyme that catalyzes the de novo biosynthesis of long-chain saturated fatty acids starting from acetyl-CoA and malonyl-CoA in the presence of NADPH. This multifunctional protein contains 7 catalytic activities and a site for the binding of the prosthetic group 4'-phosphopantetheine of the acyl carrier protein ([ACP]) domain. .
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Uniprot ID
FAS_RAT
        Click to Show/Hide the Complete Species Lineage
Kingdom: Metazoa
Phylum: Chordata
Class: Mammalia
Order: Rodentia
Family: Muridae
Genus: Rattus
Species: Rattus norvegicus
Type(s) of Resistant Mechanism of This Molecule
  MRAP: Metabolic Reprogramming via Altered Pathways
  UAPP: Unusual Activation of Pro-survival Pathway
Drug Resistance Data Categorized by Drug
Approved Drug(s)
3 drug(s) in total
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Cisplatin
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Drug Resistance Data Categorized by Their Corresponding Mechanisms
  Metabolic Reprogramming via Altered Pathways (MRAP) Click to Show/Hide
Disease Class: Bladder cancer [ICD-11: 2C94.0] [1]
Metabolic Type Lipid metabolism
Resistant Disease Bladder cancer [ICD-11: 2C94.0]
 Disease Info 
Resistant Drug Cisplatin
 Drug Info 
Molecule Alteration Expression
Up-regulation
Experimental Note Revealed Based on the Cell Line Data
In Vitro Model T24 cells Bladder Homo sapiens (Human) CVCL_0554
Experiment for
Molecule Alteration		 Western blot analysis
Experiment for
Drug Resistance		 IC50 assay
Mechanism Description Acetyl-CoA is then carboxylated into malonyl-CoA via acetyl-CoA carboxylase, and malonyl-CoA is then converted to the 16-carbon-long fatty acid palmitic acid by the enzyme FASN. Enzymes involved in fatty acid synthesis are highly expressed in many types of cancer, and their pharmacological inhibition has been shown to exert anticancer activity [43]. ATP citrate lyase and FASN upregulation has been shown in colorectal, gastric, liver, and lung cancer, and their overexpression has been significantly associated with poor survival in lung cancer patients [44, 46].
Disease Class: Bladder cancer [ICD-11: 2C94.0] [1]
Metabolic Type Lipid metabolism
Resistant Disease Bladder cancer [ICD-11: 2C94.0]
 Disease Info 
Resistant Drug Cisplatin
 Drug Info 
Molecule Alteration Expression
Up-regulation
Experimental Note Revealed Based on the Cell Line Data
In Vitro Model J82 cells Bladder Homo sapiens (Human) CVCL_0359
Experiment for
Molecule Alteration		 Western blot analysis
Experiment for
Drug Resistance		 IC50 assay
Mechanism Description Acetyl-CoA is then carboxylated into malonyl-CoA via acetyl-CoA carboxylase, and malonyl-CoA is then converted to the 16-carbon-long fatty acid palmitic acid by the enzyme FASN. Enzymes involved in fatty acid synthesis are highly expressed in many types of cancer, and their pharmacological inhibition has been shown to exert anticancer activity [43]. ATP citrate lyase and FASN upregulation has been shown in colorectal, gastric, liver, and lung cancer, and their overexpression has been significantly associated with poor survival in lung cancer patients [44, 47].
Disease Class: Bladder cancer [ICD-11: 2C94.0] [1]
Metabolic Type Lipid metabolism
Resistant Disease Bladder cancer [ICD-11: 2C94.0]
 Disease Info 
Resistant Drug Cisplatin
 Drug Info 
Molecule Alteration Expression
Up-regulation
Experimental Note Revealed Based on the Cell Line Data
In Vivo Model Five-week-old female nude mice (BALB/c nu/nu), with BC cell lines Mice
Experiment for
Molecule Alteration		 Western blot analysis
Experiment for
Drug Resistance		 Tumor weight assay
Mechanism Description Acetyl-CoA is then carboxylated into malonyl-CoA via acetyl-CoA carboxylase, and malonyl-CoA is then converted to the 16-carbon-long fatty acid palmitic acid by the enzyme FASN. Enzymes involved in fatty acid synthesis are highly expressed in many types of cancer, and their pharmacological inhibition has been shown to exert anticancer activity [43]. ATP citrate lyase and FASN upregulation has been shown in colorectal, gastric, liver, and lung cancer, and their overexpression has been significantly associated with poor survival in lung cancer patients [44, 45].
  Unusual Activation of Pro-survival Pathway (UAPP) Click to Show/Hide
Disease Class: Bladder cancer [ICD-11: 2C94.0] [2]
Resistant Disease Bladder cancer [ICD-11: 2C94.0]
 Disease Info 
Resistant Drug Cisplatin
 Drug Info 
Molecule Alteration Expression
Up-regulation
Experimental Note Revealed Based on the Cell Line Data
Cell Pathway Regulation Fatty acid biosynthesis signaling pathway Activation hsa00061
In Vitro Model T24 cells Bladder Homo sapiens (Human) CVCL_0554
J82 cells Bladder Homo sapiens (Human) CVCL_0359
In Vivo Model BALB/c female nude mice model Mus musculus
Experiment for
Molecule Alteration		 MS analysis; Western blot assay; Immunohistochemistry
Experiment for
Drug Resistance		 IC50 assay; Cell proliferation assay; Migration ability assay; Invasion ability assay; Apoptosis assay
Mechanism Description Cisplatin-resistant cells showed elevated fatty acid metabolism, upregulating fatty acid synthase (FASN) downstream of tyrosine kinase. Using the fibroblast growth factor receptor (FGFR) tyrosine kinase inhibitor erdafitinib, we inhibited malonyl-CoA production, which is crucial for fatty acid synthesis, and thereby suppressed upregulated HIF1alpha expression. Combination treatment with NCT503 and erdafitinib synergistically suppressed tumor cell proliferation and induced apoptosis in?vitro and in?vivo. Understanding these mechanisms could enable innovative BC therapeutic strategies to be developed.
Disease Class: Bladder cancer [ICD-11: 2C94.0] [2]
Resistant Disease Bladder cancer [ICD-11: 2C94.0]
 Disease Info 
Resistant Drug Cisplatin
 Drug Info 
Molecule Alteration Expression
Up-regulation
Experimental Note Revealed Based on the Cell Line Data
Cell Pathway Regulation Fatty acid biosynthesis Activation hsa00061
In Vitro Model J82 cells Bladder Homo sapiens (Human) CVCL_0359
Experiment for
Molecule Alteration		 Western blot assay
Experiment for
Drug Resistance		 Trypan blue exclusion assay; XTT assay
Mechanism Description Metabolomics analyses in our lab's gemcitabine- and cisplatin-resistant cell lines revealed increased phosphoglycerate dehydrogenase (PHGDH) expression in gemcitabine-resistant cells compared with parental cells. Isocitrate dehydrogenase 2 (IDH2) gain of function stabilized hypoxia-inducible factor1alpha (HIF1alpha) expression, stimulating aerobic glycolysis. In gemcitabine-resistant cells, elevated fumaric acid suppressed prolyl hydroxylase domain-containing protein 2/Egl nine homolog 1 (PHD2) and stabilized?HIF1alpha?expression.?PHGDH?downregulation or inhibition in gemcitabine-resistant BC cells inhibited their proliferation, migration, and invasion. Cisplatin-resistant cells showed elevated fatty acid metabolism, upregulating fatty acid synthase (FASN) downstream of tyrosine kinase. Using the fibroblast growth factor receptor (FGFR) tyrosine kinase inhibitor erdafitinib, we inhibited malonyl-CoA production, which is crucial for fatty acid synthesis, and thereby suppressed upregulated HIF1alpha expression.
Gemcitabine
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Drug Resistance Data Categorized by Their Corresponding Mechanisms
  Metabolic Reprogramming via Altered Pathways (MRAP) Click to Show/Hide
Disease Class: Bladder cancer [ICD-11: 2C94.0] [3]
Metabolic Type Lipid metabolism
Resistant Disease Bladder cancer [ICD-11: 2C94.0]
 Disease Info 
Resistant Drug Gemcitabine
 Drug Info 
Molecule Alteration Expression
Up-regulation
Experimental Note Identified from the Human Clinical Data
In Vivo Model BLCA patients Homo Sapiens
Experiment for
Molecule Alteration		 RNA sequencing
Experiment for
Drug Resistance		 Overall survival assay (OS)
Mechanism Description Further in vitro and in vivo studies were implemented using Fatty Acid Synthase (FASN), a representative gene, which promotes gemcitabine resistance, and its inhibitor (TVB-3166) that can reverse this resistance effect.
Disease Class: Bladder cancer [ICD-11: 2C94.0] [3]
Metabolic Type Lipid metabolism
Resistant Disease Bladder cancer [ICD-11: 2C94.0]
 Disease Info 
Resistant Drug Gemcitabine
 Drug Info 
Molecule Alteration Expression
Up-regulation
Experimental Note Revealed Based on the Cell Line Data
In Vitro Model T24-R cells with FASN knockdown Bladder Homo sapiens (Human) CVCL_0554
UMUC3-R cells with FASN knockdown Bladder Homo sapiens (Human) CVCL_1783
Gemcitabine-resistant UMUC3 cells Bladder Homo sapiens (Human) CVCL_1783
Normal BLCA cells Bladder Homo sapiens (Human) CVCL_6G45
Experiment for
Molecule Alteration		 RNA sequencing
Experiment for
Drug Resistance		 CCK8 assay
Mechanism Description Further in vitro and in vivo studies were implemented using Fatty Acid Synthase (FASN), a representative gene, which promotes gemcitabine resistance, and its inhibitor (TVB-3166) that can reverse this resistance effect.
Disease Class: Bladder cancer [ICD-11: 2C94.0] [3]
Metabolic Type Lipid metabolism
Resistant Disease Bladder cancer [ICD-11: 2C94.0]
 Disease Info 
Resistant Drug Gemcitabine
 Drug Info 
Molecule Alteration Expression
Up-regulation
Experimental Note Revealed Based on the Cell Line Data
In Vitro Model T24 cells Bladder Homo sapiens (Human) CVCL_0554
Experiment for
Molecule Alteration		 qRT-PCR; Western blot analysis
Experiment for
Drug Resistance		 Colony formation assay
Mechanism Description FASN, as a representative gene, was further verified as a promoting factor for gemcitabine resistance in vitro and in vivo. Previous researches have proven that the effect of a FASN inhibitor (TVB-3166) on carcinogenic signals and gene expression enhances the antitumor efficacy of various xenograft tumor models [37]. Our study further demonstrated that TVB-3166 can reverse gemcitabine resistance.
Tamoxifen
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Drug Resistance Data Categorized by Their Corresponding Mechanisms
  Metabolic Reprogramming via Altered Pathways (MRAP) Click to Show/Hide
Disease Class: Breast adenocarcinoma [ICD-11: 2C60.1] [4]
Metabolic Type Lipid metabolism
Resistant Disease Breast adenocarcinoma [ICD-11: 2C60.1]
 Disease Info 
Resistant Drug Tamoxifen
 Drug Info 
Molecule Alteration Expression
Up-regulation
Experimental Note Identified from the Human Clinical Data
In Vivo Model HCC patients Homo Sapiens
Experiment for
Molecule Alteration		 Western blot analysis
Mechanism Description Our results revealed that FASN predominates under sensitive conditions, crucially contributing to aerobic respiration. However, its activity diminishes in advanced stages and in tamoxifen-resistant conditions. Conversely, the progressive upregulation of LDHA and the prevalence of anaerobic respiration emerged as metabolic signatures associated with the acquisition of tamoxifen resistance. Subsequently, we delineated the functional roles and metabolic adaptability in response to the inhibition of FASN and LDHA using cellular models representative of tamoxifen-resistant BC.
Disease Class: Breast adenocarcinoma [ICD-11: 2C60.1] [4]
Metabolic Type Lipid metabolism
Resistant Disease Breast adenocarcinoma [ICD-11: 2C60.1]
 Disease Info 
Resistant Drug Tamoxifen
 Drug Info 
Molecule Alteration Expression
Up-regulation
Experimental Note Revealed Based on the Cell Line Data
In Vitro Model MCF-10A cells Breast Homo sapiens (Human) CVCL_0598
MCF-7 TamR cells Breast Homo sapiens (Human) CVCL_0031
MCF7 cells Breast Homo sapiens (Human) CVCL_0031
MDA-MB-231cells Breast Homo sapiens (Human) CVCL_0062
Experiment for
Molecule Alteration		 Western blot analysis
Experiment for
Drug Resistance		 Cell viability assay
Mechanism Description Our results revealed that FASN predominates under sensitive conditions, crucially contributing to aerobic respiration. However, its activity diminishes in advanced stages and in tamoxifen-resistant conditions. Conversely, the progressive upregulation of LDHA and the prevalence of anaerobic respiration emerged as metabolic signatures associated with the acquisition of tamoxifen resistance. Subsequently, we delineated the functional roles and metabolic adaptability in response to the inhibition of FASN and LDHA using cellular models representative of tamoxifen-resistant BC.
Preclinical Drug(s)
1 drug(s) in total
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TVB-3166
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Drug Sensitivity Data Categorized by Their Corresponding Mechanisms
  Metabolic Reprogramming via Altered Pathways (MRAP) Click to Show/Hide
Disease Class: Bladder cancer [ICD-11: 2C94.0] [3]
Metabolic Type Lipid metabolism
Sensitive Disease Bladder cancer [ICD-11: 2C94.0]
 Disease Info 
Sensitive Drug TVB-3166
 Drug Info 
Molecule Alteration Expression
Down-regulation
Experimental Note Revealed Based on the Cell Line Data
In Vitro Model T24 cells Bladder Homo sapiens (Human) CVCL_0554
UMUC3-R cells Bladder Homo sapiens (Human) CVCL_1783
Experiment for
Molecule Alteration		 RNA sequencing
Experiment for
Drug Resistance		 CCK8 assay
Mechanism Description Further in vitro and in vivo studies were implemented using Fatty Acid Synthase (FASN), a representative gene, which promotes gemcitabine resistance, and its inhibitor (TVB-3166) that can reverse this resistance effect.
Investigative Drug(s)
1 drug(s) in total
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Cerulenin
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Drug Sensitivity Data Categorized by Their Corresponding Mechanisms
  Metabolic Reprogramming via Altered Pathways (MRAP) Click to Show/Hide
Disease Class: Hepatocellular carcinoma [ICD-11: 2C12.02] [5]
Metabolic Type Lipid metabolism
Sensitive Disease Hepatocellular carcinoma [ICD-11: 2C12.02]
 Disease Info 
Sensitive Drug Cerulenin
 Drug Info 
Molecule Alteration Expression
Up-regulation
Experimental Note Revealed Based on the Cell Line Data
In Vitro Model HepG2/C3A cells Liver Homo sapiens (Human) CVCL_0027
Huh7 cells Kidney Homo sapiens (Human) CVCL_U442
Experiment for
Molecule Alteration		 qRT-PCR; Western blot analysis
Experiment for
Drug Resistance		 Cell viability assay
Mechanism Description Importantly, our RNA sequencing analysis disclosed that the amyloid protein precursor (APP) is a crucial downstream effector of FASN in regulating CSC properties. We found that APP plays a crucial role in CSCs' characteristics that can be inhibited by cerulenin.
References
Ref 1 Targeting metabolic reprogramming to overcome drug resistance in advanced bladder cancer: insights from gemcitabine- and cisplatin-resistant models. Mol Oncol. 2024 Sep;18(9):2196-2211.
Ref 2 Targeting metabolic reprogramming to overcome drug resistance in advanced bladder cancer: insights from gemcitabine- and cisplatin-resistant models. Mol Oncol. 2024 Sep;18(9):2196-2211.
Ref 3 Metabolic reprogramming based on RNA sequencing of gemcitabine-resistant cells reveals the FASN gene as a therapeutic for bladder cancer. J Transl Med. 2024 Jan 13;22(1):55.
Ref 4 Inverse FASN and LDHA correlation drives metabolic resistance in breast cancer. J Transl Med. 2024 Jul 24;22(1):676.
Ref 5 Fatty acid synthase inhibitor cerulenin hinders liver cancer stem cell properties through FASN/APP axis as novel therapeutic strategies. J Lipid Res. 2024 Nov;65(11):100660.

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