| 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: |
Università degli Studi dell'Aquila = University of L'Aquila = Université de L'Aquila (UNIVAQ); Imperial College London; Università degli Studi di Perugia = University of Perugia (UNIPG); Protéomique, Réponse Inflammatoire, Spectrométrie de Masse (PRISM) - U 1192 (PRISM); Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire CHU Lille (CHRU Lille) |
| Source: |
ISSN: 1558-8238 ; The Journal of clinical investigation ; https://hal.univ-lille.fr/hal-04019357 ; The Journal of clinical investigation, 2021, 131 (11), pp.e137845. ⟨10.1172/JCI137845⟩. |
| Publisher Information: |
CCSD; American Society for Clinical Investigation |
| Publication Year: |
2021 |
| Collection: |
LillOA (HAL Lille Open Archive, Université de Lille) |
| Subject Terms: |
[SDV]Life Sciences [q-bio] |
| Description: |
International audience ; 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. |
| Document Type: |
article in journal/newspaper |
| Language: |
English |
| Relation: |
info:eu-repo/semantics/altIdentifier/pmid/33878036; PUBMED: 33878036 |
| DOI: |
10.1172/JCI137845 |
| Availability: |
https://hal.univ-lille.fr/hal-04019357; https://hal.univ-lille.fr/hal-04019357v1/document; https://hal.univ-lille.fr/hal-04019357v1/file/2021-04-20-137845.2-20210520182818-covered-e0fd13ba177f913fd3156f593ead4cfd.pdf; https://doi.org/10.1172/JCI137845 |
| Rights: |
http://creativecommons.org/licenses/by/ ; info:eu-repo/semantics/OpenAccess |
| Accession Number: |
edsbas.D69B74AF |
| Database: |
BASE |