PMID- 32913236
OWN - NLM
STAT- MEDLINE
DCOM- 20210325
LR  - 20210910
IS  - 2045-2322 (Electronic)
IS  - 2045-2322 (Linking)
VI  - 10
IP  - 1
DP  - 2020 Sep 10
TI  - Membrane disruption, but not metabolic rewiring, is the key mechanism of 
      anticancer-action of FASN-inhibitors: a multi-omics analysis in ovarian cancer.
PG  - 14877
LID - 10.1038/s41598-020-71491-z [doi]
LID - 14877
AB  - Fatty-acid(FA)-synthase(FASN) is a druggable lipogenic oncoprotein whose blockade 
      causes metabolic disruption. Whether drug-induced metabolic perturbation is 
      essential for anticancer drug-action, or is just a secondary-maybe even a defence 
      response-is still unclear. To address this, SKOV3 and OVCAR3 ovarian cancer(OC) 
      cell lines with clear cell and serous histology, two main OC subtypes, were 
      exposed to FASN-inhibitor G28UCM. Growth-inhibition was compared with 
      treatment-induced cell-metabolomes, lipidomes, proteomes and kinomes. SKOV3 and 
      OVCAR3 were equally sensitive to low-dose G28UCM, but SKOV3 was more resistant 
      than OVCAR3 to higher concentrations. Metabolite levels generally decreased upon 
      treatment, but individual acylcarnitines, glycerophospholipids, sphingolipids, 
      amino-acids, biogenic amines, and monosaccharides reacted differently. 
      Drug-induced effects on central-carbon-metabolism and oxidative-phosphorylation 
      (OXPHOS) were essentially different in the two cell lines, since drug-naive SKOV3 
      are known to prefer glycolysis, while OVCAR3 favour OXPHOS. Moreover, 
      drug-dependent increase of desaturases and polyunsaturated-fatty-acids (PUFAs) 
      were more pronounced in SKOV3 and appear to correlate with G28UCM-tolerance. In 
      contrast, expression and phosphorylation of proteins that control apoptosis, FA 
      synthesis and membrane-related processes (beta-oxidation, membrane-maintenance, 
      transport, translation, signalling and stress-response) were concordantly 
      affected. Overall, membrane-disruption and second-messenger-silencing were 
      crucial for anticancer drug-action, while metabolic-rewiring was only secondary 
      and may support high-dose-FASN-inhibitor-tolerance. These findings may guide 
      future anti-metabolic cancer intervention.
FAU - Grunt, Thomas W
AU  - Grunt TW
AD  - Cell Signaling and Metabolism Networks Program, Division of Oncology, Department 
      of Medicine I, Medical University of Vienna, Waehringer Guertel 18-20, 1090, 
      Vienna, Austria. thomas.grunt@meduniwien.ac.at.
AD  - Comprehensive Cancer Center, Vienna, Austria. thomas.grunt@meduniwien.ac.at.
AD  - Ludwig Boltzmann Institute for Hematology and Oncology, Vienna, Austria. 
      thomas.grunt@meduniwien.ac.at.
FAU - Slany, Astrid
AU  - Slany A
AD  - Department of Analytical Chemistry, University of Vienna, Vienna, Austria.
FAU - Semkova, Mariya
AU  - Semkova M
AD  - Department of Analytical Chemistry, University of Vienna, Vienna, Austria.
FAU - Colomer, Ramon
AU  - Colomer R
AD  - Department of Medical Oncology, Hospital Universitario La Princesa and Spanish 
      National Cancer Research Centre (CNIO), Clinical Research Program, Madrid, Spain.
FAU - Lopez-Rodriguez, Maria Luz
AU  - Lopez-Rodriguez ML
AD  - Departamento de Quimica Organica I, Facultad de Ciencias Quimicas, Universidad 
      Complutense de Madrid, Madrid, Spain.
FAU - Wuczkowski, Michael
AU  - Wuczkowski M
AD  - Department of Biomedical Imaging and Image-Guided Therapy, Medical University of 
      Vienna, Vienna, Austria.
FAU - Wagner, Renate
AU  - Wagner R
AD  - Cell Signaling and Metabolism Networks Program, Division of Oncology, Department 
      of Medicine I, Medical University of Vienna, Waehringer Guertel 18-20, 1090, 
      Vienna, Austria.
AD  - Comprehensive Cancer Center, Vienna, Austria.
FAU - Gerner, Christopher
AU  - Gerner C
AD  - Department of Analytical Chemistry, University of Vienna, Vienna, Austria.
FAU - Stubiger, Gerald
AU  - Stubiger G
AD  - Comprehensive Cancer Center, Vienna, Austria.
AD  - Department of Biomedical Imaging and Image-Guided Therapy, Medical University of 
      Vienna, Vienna, Austria.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20200910
PL  - England
TA  - Sci Rep
JT  - Scientific reports
JID - 101563288
RN  - 0 (1,3-bis((3,4,5-trihydroxybenzoyl)oxy)naphthalene)
RN  - 0 (Fatty Acid Synthesis Inhibitors)
RN  - 0 (Naphthalenes)
RN  - 0 (Proteome)
RN  - 632XD903SP (Gallic Acid)
RN  - EC 2.3.1.85 (FASN protein, human)
RN  - EC 2.3.1.85 (Fatty Acid Synthase, Type I)
SB  - IM
MH  - Cell Line, Tumor
MH  - Cell Membrane/chemistry/*drug effects/metabolism
MH  - Cell Proliferation
MH  - Drug Resistance, Neoplasm
MH  - Fatty Acid Synthase, Type I/*antagonists & inhibitors/metabolism
MH  - Fatty Acid Synthesis Inhibitors/pharmacology
MH  - Female
MH  - Gallic Acid/*analogs & derivatives/pharmacology
MH  - Humans
MH  - Lipidomics/*methods
MH  - Metabolome
MH  - Naphthalenes/*pharmacology
MH  - Ovarian Neoplasms/*drug therapy/metabolism/pathology
MH  - Proteome/*metabolism
MH  - Signal Transduction
PMC - PMC7483762
COIS- The authors declare no competing interests.
EDAT- 2020/09/12 06:00
MHDA- 2021/03/26 06:00
PMCR- 2020/09/10
CRDT- 2020/09/11 05:41
PHST- 2020/01/13 00:00 [received]
PHST- 2020/07/15 00:00 [accepted]
PHST- 2020/09/11 05:41 [entrez]
PHST- 2020/09/12 06:00 [pubmed]
PHST- 2021/03/26 06:00 [medline]
PHST- 2020/09/10 00:00 [pmc-release]
AID - 10.1038/s41598-020-71491-z [pii]
AID - 71491 [pii]
AID - 10.1038/s41598-020-71491-z [doi]
PST - epublish
SO  - Sci Rep. 2020 Sep 10;10(1):14877. doi: 10.1038/s41598-020-71491-z.