| Title: |
Enhanced triacylglycerol catabolism by carboxylesterase 1 promotes aggressive colorectal carcinoma |
| Authors: |
Capece, Daria; D'andrea, Daniel; Begalli, Federica; Goracci, Laura; Tornatore, Laura; Alexander, James L.; Di Veroli, Alessandra; Leow, Shi-Chi; Vaiyapuri, Thamil S.; Ellis, James K.; Verzella, Daniela; Bennett, Jason; Savino, Luca; Ma, Yue; Mckenzie, James S.; Doria, Maria Luisa; Mason, Sam E.; Chng, Kern Rei; Keun, Hector C.; Frost, Gary; Tergaonkar, Vinay; Broniowska, Katarzyna; Stunkel, Walter; Takats, Zoltan; Kinross, James M.; Cruciani, Gabriele; Franzoso, Guido |
| Contributors: |
INSERM; Université de Lille; Protéomique, Réponse Inflammatoire, Spectrométrie de Masse (PRISM) - U1192; Università degli Studi dell'Aquila = University of L'Aquila UNIVAQ; Imperial College London; Università degli Studi di Perugia = University of Perugia UNIPG |
| Publication Year: |
2023 |
| Collection: |
LillOA (Lille Open Archive - Université de Lille) |
| Description: |
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-kappaB transcription factor pathway associates with advanced disease stages and shorter survival in patients with CRC. NF-kappaB 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-kappaB affects the metabolic adaptations that fuel aggressive disease in patients with CRC is unknown. Here, we identified carboxylesterase 1 (CES1) as an essential NF-kappaB-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-kappaB 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. ; 131;11 |
| Document Type: |
article in journal/newspaper |
| File Description: |
application/octet-stream; application/rdf+xml; charset=utf-8 |
| Language: |
English |
| Relation: |
The Journal of clinical investigation; J Clin Invest; http://hdl.handle.net/20.500.12210/75043 |
| Availability: |
https://hdl.handle.net/20.500.12210/75043 |
| Rights: |
Attribution 3.0 United States ; info:eu-repo/semantics/openAccess |
| Accession Number: |
edsbas.CF7FEB5C |
| Database: |
BASE |