Abstract
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-naïve 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.
Highlights
Fatty-acid(FA)-synthase(FASN) is a druggable lipogenic oncoprotein whose blockade causes metabolic disruption
Consistent with our previous studies[8,9], after 72 h drug exposure the IC50 value in each cell line was in the low μM range, demonstrating that both are highly sensitive to fatty acid synthase (FASN) inhibition
Fatty acid synthase (FASN), the key enzyme that controls the biosynthesis of fatty acids and lipids, for example, is overexpressed in most tumours and correlates with malignant p rogression[3,14]
Summary
Fatty-acid(FA)-synthase(FASN) is a druggable lipogenic oncoprotein whose blockade causes metabolic disruption. 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. Treatment with FASN inhibitors is necessarily associated with severe metabolic aberrations in the cancer cells It is still unclear whether these metabolic changes are the primary cause or just a secondary consequence of the cytotoxic action of FASN blocking drugs. We compared the metabolomes of SKOV3 and OVCAR3 cells in the presence or absence of G28UCM with the corresponding proteomes and kinomes Based on this multi-omics approach and the establishment of ‘SKOV3/OVCAR3 Matching Scores’, we were able to show that the anticancer effect of the FASN inhibitor is mainly due to damage to the lipid bilayer and blockade of lipid signalling, and only secondarily to a deterioration of the central cell metabolism. Deterioration of lipid membranes appears as the causative primary anticancer event, whereas metabolic perturbation seems to be only a consequence thereof
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