1. Model-driven discovery of long-chain fatty acid metabolic reprogramming in heterogeneous prostate cancer cells.
- Author
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Marín de Mas, Igor, Aguilar, Esther, Zodda, Erika, Balcells, Cristina, Marin, Silvia, Dallmann, Guido, Thomson, Timothy M., Papp, Balázs, and Cascante, Marta
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PROSTATE cancer , *CANCER cells , *CELL lines , *NEOVASCULARIZATION , *FATTY acids , *CELL proliferation , *CELL adhesion - Abstract
Epithelial-mesenchymal-transition promotes intra-tumoral heterogeneity, by enhancing tumor cell invasiveness and promoting drug resistance. We integrated transcriptomic data for two clonal subpopulations from a prostate cancer cell line (PC-3) into a genome-scale metabolic network model to explore their metabolic differences and potential vulnerabilities. In this dual cell model, PC-3/S cells express Epithelial-mesenchymal-transition markers and display high invasiveness and low metastatic potential, while PC-3/M cells present the opposite phenotype and higher proliferative rate. Model-driven analysis and experimental validations unveiled a marked metabolic reprogramming in long-chain fatty acids metabolism. While PC-3/M cells showed an enhanced entry of long-chain fatty acids into the mitochondria, PC-3/S cells used long-chain fatty acids as precursors of eicosanoid metabolism. We suggest that this metabolic reprogramming endows PC-3/M cells with augmented energy metabolism for fast proliferation and PC-3/S cells with increased eicosanoid production impacting angiogenesis, cell adhesion and invasion. PC-3/S metabolism also promotes the accumulation of docosahexaenoic acid, a long-chain fatty acid with antiproliferative effects. The potential therapeutic significance of our model was supported by a differential sensitivity of PC-3/M cells to etomoxir, an inhibitor of long-chain fatty acid transport to the mitochondria. [ABSTRACT FROM AUTHOR]
- Published
- 2018
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