Global metabolite profiling analysis of lipotoxicity in HER2/neu-positive breast cancer cells

Abstract

Recent work has shown that HER2/neu-positive breast cancer cells rely on a unique Warburg-like metabolism for survival and aggressive behavior. These cells are dependent on fatty acid (FA) synthesis, show markedly increased levels of stored fats and disruption of the synthetic process results in apoptosis. In this study, we used global metabolite profiling and a multi-omics network analysis approach to model the metabolic changes in this physiology under palmitate-supplemented growth conditions to gain insights into the molecular mechanism and its relevance to disease prevention and treatment. Computational analyses were used to define pathway enrichment based on the dataset of significantly altered metabolites and to integrate metabolomics and transcriptomics data in a multi-omics network analysis. Network-predicted changes and functional relationships were tested with cell assays in vitro. Palmitate-supplemented growth conditions induce distinct metabolic alterations. Growth of HER2-normal MCF7 cells is unaffected under these conditions whereas HER2/neu-positive cells display unchanged neutral lipid content, AMPK activation, inhibition of fatty acid synthesis and significantly altered glutamine, glucose and serine/glycine metabolism. The predominant upregulated lipid species is the novel bioactive lipid N-palmitoylglycine, which is non-toxic to these cells. Limiting the availability of glutamine significantly ameliorates the lipotoxic effects of palmitate, reduces CHOP and XBP1(s) induction and restores the expression levels of HER2 and HER3. The study shows that HER2/neu-positive breast cancer cells change their metabolic phenotype in the presence of palmitate. Palmitate induces AMPK activation and inhibition of fatty acid synthesis that feeds back into glycolysis as well as anaplerotic glutamine metabolism.