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Enhanced triacylglycerol catabolism by carboxylesterase 1 promotes aggressive colorectal carcinoma
- Source :
- Journal of Clinical Investigation. June 1, 2021, Vol. 131 Issue 11
- Publication Year :
- 2021
-
Abstract
- The ability to adapt to low-nutrient microenvironments is essential for tumor cell survival and progression in solid cancers, such as colorectal carcinoma (CRC). Signaling by the NF-[kappa]B transcription factor pathway associates with advanced disease stages and shorter survival in patients with CRC. NF-[kappa]B has been shown to drive tumor-promoting inflammation, cancer cell survival, and intestinal epithelial cell (IEC) dedifferentiation in mouse models of CRC. However, whether NF-[kappa]B affects the metabolic adaptations that fuel aggressive disease in patients with CRC is unknown. Here, we identified carboxylesterase 1 (CES1) as an essential NF-[kappa]B-regulated lipase linking obesity-associated inflammation with fat metabolism and adaptation to energy stress in aggressive CRC. CES1 promoted CRC cell survival via cell-autonomous mechanisms that fuel fatty acid oxidation (FAO) and prevent the toxic build-up of triacylglycerols. We found that elevated CES1 expression correlated with worse outcomes in overweight patients with CRC. Accordingly, NF-[kappa]B drove CES1 expression in CRC consensus molecular subtype 4 (CMS4), which is associated with obesity, stemness, and inflammation. CES1 was also upregulated by gene amplifications of its transcriptional regulator HNF4A in CMS2 tumors, reinforcing its clinical relevance as a driver of CRC. This subtype-based distribution and unfavorable prognostic correlation distinguished CES1 from other intracellular triacylglycerol lipases and suggest CES1 could provide a route to treat aggressive CRC.<br />Introduction Tumor cells must adapt to the low nutrient concentrations in the tumor microenvironment (TME) in order to survive, proliferate, and spread to distant sites (1-4). The availability of nutrients, [...]
Details
- Language :
- English
- ISSN :
- 00219738
- Volume :
- 131
- Issue :
- 11
- Database :
- Gale General OneFile
- Journal :
- Journal of Clinical Investigation
- Publication Type :
- Academic Journal
- Accession number :
- edsgcl.664447460
- Full Text :
- https://doi.org/10.1172/JCI137845