Metabolomic Analysis Points to Bioactive Lipid Species and Acireductone Dioxygenase 1 (ADI1) as Potential Therapeutic Targets in Poor Prognosis Endometrial Cancer

Abstract

Metabolomic profiling analysis has the potential to highlight new molecules and cellular pathways that may serve as potential therapeutic targets for disease treatment. In this study, we used an LC-MS/MS platform to define, for the first time, the specific metabolomic signature of uterine serous carcinoma (SC), a relatively rare and aggressive variant of endometrial cancer (EC) responsible for 40% of all endometrial cancer-related deaths. A metabolomic analysis of 31 ECs (20 endometrial endometrioid carcinomas (EECs) and 11 SCs) was performed. Following multivariate statistical analysis, we identified 232 statistically different metabolites among the SC and EEC patient samples. Notably, most of the metabolites identified (89.2%) were lipid species and showed lower levels in SCs when compared to EECs. In addition to lipids, we also documented metabolites belonging to amino acids and purine nucleotides (such as 2-Oxo-4-methylthiobutanoic acid, synthesised by acireductone dioxygenase 1 (ADI1) enzyme), which showed higher levels in SCs. To further investigate the role of ADI1 in SC, we analysed the expression protein levels of ADI1 in 96 ECs (67 EECs and 29 SCs), proving that the levels of ADI1 were higher in SCs compared to EECs. We also found that ADI1 mRNA levels were higher in p53 abnormal ECs compared to p53 wild type tumours. Furthermore, elevated ADI1 mRNA levels showed a statistically significant negative correlation with overall survival and progression-free survival among EEC patients. Finally, we tested the ability of ADI1 to induce migration and invasion capabilities in EC cell lines. Altogether, these results suggest that ADI1 could be a potential therapeutic target in poor-prognosis SCs and other Ecs with abnormal p53 expression.

Endometrial cancer diagnostic and prognostic algorithms based on proteomics, metabolomics, and clinical data: a systematic review

“…Comparison of metabolic profiles in tissue samples to urine and brushing samples showed that 49 of 74 metabolites were also detected in urine samples and 21 of 74 metabolites in intrauterine brushing samples, which supports the potential of urine metabolomics profiles for non-invasive diagnostic/prognosis ( Supplementary Table S8 ). A recent study explored the metabolic profiles in biobanked tissue samples from endometrioid (n=20) and serous EC (n=11) ( 153 ). Using non-targeted MS analysis, 232 metabolic differences could be characterised ( Supplementary Table S8 ).…”

Metabolism pathway-based subtyping in endometrial cancer: An integrated study by multi-omics analysis and machine learning algorithms

“…Metabolomics studies also revealed that arachidonic acid, stearic acid, and linoleic acid metabolites enrolled in lipid metabolism were lowered in advanced-stage and nonendometrioid EC samples. 60 , 61 , 62 Building upon the insights gained from multi-omics analysis, we hypothesized that focusing on subtype-specific metabolic characteristics that significantly influence tumor behavior within the MPS subtypes may provide useful targeted therapy strategies in EC, but these need further validation in the future.…”

Metabolomics for Clinical Biomarker Discovery and Therapeutic Target Identification

“…The increased concentrations of microbially derived tryptophan and propionate can cause mitigation of gastrointestinal syndromes, long-term radioprotection, and reduction in proinflammatory responses [112]. Different metabolites among the uterine serous carcinoma and endometrial cancer were discovered, and most belonged to purine nucleotides and amino acids, including 2-oxo-4-methylthiobutanoic acid synthesized via the acireductone dioxygenase 1 enzyme, which are potential therapeutic targets in poor-prognosis serous carcinoma patients [113].…”