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 6

CES1-dependent metabolic adaptation is reciprocally controlled by NF-κB and HNF4α in distinct CRCs.

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CES1-dependent metabolic adaptation is reciprocally controlled by NF-κB ...
(A) qRT-PCR showing CES1 mRNA expression in the indicated human CRC cell lines expressing RELA-specific (RELA) or ns shRNAs. (B) Heatmap showing the log2 fold change of metabolic species in the indicated lipid classes in RELA-deficient (RELA) relative to control cells in the indicated human CRC cell lines, cultured under normal conditions (0) or GL for 4 days, identified by LC-MS and Lipostar software. Shown are the lipids having a value different from zero at the time points investigated. Orange, increased abundance; azure, decreased abundance. Statistical significance of the lipid accumulation during GL was determined by a hypergeometric test, corrected using the Benjamini-Hochberg procedure (triacylglycerols in RKO cells at d4, q = 5.47 × 10–32). (C) Trypan blue exclusion assays showing the percentage of live cells from the indicated human CRC cell lines expressing CES1-specific (CES1) or ns shRNAs after a 4-day culture under GL (top). Western blots showing CES1 and β-actin protein levels in the same cells (bottom). (D) qRT-PCR showing the CES1 mRNA expression in the human CRC cell lines from A expressing HNF4A-specific (HNF4A) or ns shRNAs. (E) Trypan blue exclusion assays showing the percentage of live cells from the indicated human CRC cell lines after a 4-day treatment with GR-148672X (10 μM) or vehicle during GL (top). Values denote mean ± SD (n = 3). Images of representative cells (bottom). Scale bar: 50 μm. (A and D) Experiments were conducted twice. (C and E) Experiments were conducted at least 3 times. (A and C–E) Values denote mean ± SD (n = 3). Statistical significance was calculated by 2-tailed Student’s t test. **P < 0.01; ***P < 0.001.