Enhanced triacylglycerol catabolism by carboxylesterase 1 promotes aggressive colorectal carcinoma
Daria Capece, … , Gabriele Cruciani, Guido Franzoso
Daria Capece, … , Gabriele Cruciani, Guido Franzoso
Published April 20, 2021
Citation Information: J Clin Invest. 2021;131(11):e137845. https://doi.org/10.1172/JCI137845.
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Research Article Metabolism Oncology

Enhanced triacylglycerol catabolism by carboxylesterase 1 promotes aggressive colorectal carcinoma

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-κB transcription factor pathway associates with advanced disease stages and shorter survival in patients with CRC. NF-κB 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-κB affects the metabolic adaptations that fuel aggressive disease in patients with CRC is unknown. Here, we identified carboxylesterase 1 (CES1) as an essential NF-κB–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-κB 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.

Authors

Daria Capece, Daniel D’Andrea, Federica Begalli, Laura Goracci, Laura Tornatore, James L. Alexander, Alessandra Di Veroli, Shi-Chi Leow, Thamil S. Vaiyapuri, James K. Ellis, Daniela Verzella, Jason Bennett, Luca Savino, Yue Ma, James S. McKenzie, Maria Luisa Doria, Sam E. Mason, Kern Rei Chng, Hector C. Keun, Gary Frost, Vinay Tergaonkar, Katarzyna Broniowska, Walter Stunkel, Zoltan Takats, James M. Kinross, Gabriele Cruciani, Guido Franzoso

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Figure 4

Ces1d mediates NF-κB–dependent metabolic adaptation by enhancing FFA catabolism and preventing TAG accumulation.

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Ces1d mediates NF-κB–dependent metabolic adaptation by enhancing FFA cat...
(A and B) Relative TAG (A; n = 92) and CE (B; n = 9) abundance in CT-26 cells expressing Ces1d or ns shRNAs at baseline (0) or under GL. (C) Western blots with cells from A. (D) TAG turnover, reporting the percentage of decrease of [13C]-labeled TAG abundance (n = 40) at 1 versus 0 hours, in cells from A. (E and F) Trypan blue exclusion showing the percentage of live CT-26 cells from A (E) or after a 4-day treatment as indicated (F) under normal (–) or GL conditions. (G) Trypan blue exclusion showing the percentage of live RelA-deficient or control CT-26 cells expressing eGFP or Ces1d after 4 days under GL. (H–J) SRC (H), mito-ATP (I), and nonmitochondrial OCR (J) in cells from A treated as shown. (K–O) FACS showing ROS levels (K), GSH levels (L), lipid peroxidation (M), loss of mitochondrial potential (ΔΨm) (N), and annexin V/7-AAD positivity (O) in cells from A after 2 (O), 3 (K and N) or 4 (L and M) days under GL. (P) Propidium iodide staining showing apoptotic DNA fragmentation in cells from A after 4 days under GL. (Q) Trypan blue exclusion showing the percentage of live cells from A treated as indicated after 4 days under GL. (A, B, and D) Shown are the medians (horizontal lines), 25th to 75th percentiles (box outlines), and highest and lowest values within 1.5 times the interquartile range (vertical lines). (E, F, and Q) Values denote means ± SD (n = 3). (H–J) Values denote means ± SEM (n = 6). (A, B, D–J, and Q) Significance was calculated by 2-tailed Student’s t test. *P < 0.05; **P < 0.01; ***P < 0.001.