Journal of experimental & clinical cancer research : CR · 2026
Carboxylesterase 1 is a core metabolic vulnerability of platinum-resistant high-grade serous ovarian carcinoma.
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Flati Irene, Vecchiotti Davide, Di Giovanni Fiorenza, Verzella Daniela, Dall'Aglio Francesca, Sarra Angelo, Battistini Chiara, Zambuto Melissa, Frisullo Giuseppe, Cornice Jessica, Nunzi Ilaria, Di Vito Nolfi Mauro, Whitwell Harry J, Veglianti Francesca, Khan Hafiz Nadeem, Marchi Saverio, Franzoso Guido, Cavallaro Ugo, D'Andrea Daniel, Alesse Edoardo, Zazzeroni Francesca, Capece Daria
Аннотация
BACKGROUND: Platinum-resistant high-grade serous ovarian carcinoma (HGSOC) is a major clinical challenge, with high mortality rates and no effective therapeutic options. Metabolic adaptations-including enhanced lipid catabolism, oxidative phosphorylation (OXPHOS), and autophagy-are major drivers of chemoresistance; however, the molecular mechanisms underpinning this metabolic reprogramming remain poorly understood. Carboxylesterase 1 (CES1), an NF-κB-regulated neutral lipase, supports malignant cell survival under nutrient-depleted conditions in other cancers, but its role in HGSOC has not been explored.
METHODS: We investigated the role of CES1 in i) epithelial ovarian cancer (EOC) cell lines across different histological subtypes, ii) primary HGSOC cells, iii) syngeneic and platinum-resistant HGSOC mouse models. Glucose and serum limitation was used to model metabolic stress associated with platinum resistance. CES1 activity was blocked both genetically and pharmacologically using the specific CES1 inhibitor GR-148672X. Metabolic profiling, survival analysis, lipid-droplet dynamics and autophagy assays were performed. Clinical significance was evaluated by analyzing The Cancer Genome Atlas (TCGA) cohort, stratified by chemotherapy response.
RESULTS: Metabolic stress induced a shift from glycolysis to OXPHOS and promoted platinum resistance in EOC cells. This adaptation was coincident with an upregulation of CES1, which supported lipolysis, fatty acid oxidation, and autophagy/lipophagy. CES1 inhibition disrupted these processes leading to apoptosis/ferroptosis in platinum-resistant EOC lines. Oleate supplementation effectively reversed CES1-mediated biological effects, confirming their dependence on CES1-driven lipid mobilization. CES1 blockade also killed primary HGSOC cells with oxidative dependency for survival, impaired tumor growth and metastatic dissemination in Trp53-/- ID8-Luc allografts and retained robust antitumor activity in platinum-resistant HGSOC xenografts. Further, in the TCGA dataset, an elevated CES1/Carnitine Palmitoyl-transferase 1A (CPT1A) gene signature correlated with shorter overall survival (OS) and disease-specific survival (DSS) in chemoresistant, but not chemosensitive patients with HGSOC, underscoring the clinical significance of this metabolic axis in platinum resistance.
CONCLUSIONS: CES1 is a key checkpoint governing metabolic plasticity in EOC including HGSOC, by linking lipid catabolism, OXPHOS, and autophagy to chemoresistance under conditions of metabolic pressure. Targeting CES1 selectively compromises tumor cell survival under nutrient deprivation, uncovering a metabolic vulnerability that may be exploited to treat aggressive platinum-resistant HGSOC that rely on OXPHOS to thrive.
METHODS: We investigated the role of CES1 in i) epithelial ovarian cancer (EOC) cell lines across different histological subtypes, ii) primary HGSOC cells, iii) syngeneic and platinum-resistant HGSOC mouse models. Glucose and serum limitation was used to model metabolic stress associated with platinum resistance. CES1 activity was blocked both genetically and pharmacologically using the specific CES1 inhibitor GR-148672X. Metabolic profiling, survival analysis, lipid-droplet dynamics and autophagy assays were performed. Clinical significance was evaluated by analyzing The Cancer Genome Atlas (TCGA) cohort, stratified by chemotherapy response.
RESULTS: Metabolic stress induced a shift from glycolysis to OXPHOS and promoted platinum resistance in EOC cells. This adaptation was coincident with an upregulation of CES1, which supported lipolysis, fatty acid oxidation, and autophagy/lipophagy. CES1 inhibition disrupted these processes leading to apoptosis/ferroptosis in platinum-resistant EOC lines. Oleate supplementation effectively reversed CES1-mediated biological effects, confirming their dependence on CES1-driven lipid mobilization. CES1 blockade also killed primary HGSOC cells with oxidative dependency for survival, impaired tumor growth and metastatic dissemination in Trp53-/- ID8-Luc allografts and retained robust antitumor activity in platinum-resistant HGSOC xenografts. Further, in the TCGA dataset, an elevated CES1/Carnitine Palmitoyl-transferase 1A (CPT1A) gene signature correlated with shorter overall survival (OS) and disease-specific survival (DSS) in chemoresistant, but not chemosensitive patients with HGSOC, underscoring the clinical significance of this metabolic axis in platinum resistance.
CONCLUSIONS: CES1 is a key checkpoint governing metabolic plasticity in EOC including HGSOC, by linking lipid catabolism, OXPHOS, and autophagy to chemoresistance under conditions of metabolic pressure. Targeting CES1 selectively compromises tumor cell survival under nutrient deprivation, uncovering a metabolic vulnerability that may be exploited to treat aggressive platinum-resistant HGSOC that rely on OXPHOS to thrive.