Objectives Over 80% of ovarian cancer (OC) patients will experience relapse after an initial response to platinum-based chemotherapy. Acquisition of metabolomic adaptations is thought to be an integral part of chemoresistance, but the relation of these adaptations to chemoresistance is poorly understood. Our aim was to identify the metabolic adaptations that are specifically associated with platinum-resistant (PR) cell lines and its platinum-sensitive (PS) derivatives across multiple OC cell lines.
Methods Targeted metabolic analysis evaluating 242 metabolites of the PS A2780, PEO1, and mR182 cell lines was performed along with their respective PR derivatives, C200, PEO4, R182. The group comparison was performed using unpaired t-tests followed by FDR correction. The differentially expressed metabolites were identified using two criteria: FDR ≤ 5% and absolute fold-change ≥ 1.5. The pathway analysis was performed using MetaboanalystTM with the metabolites that have unadjusted p-value ≤5%.
Results Many significantly impacted pathways were conserved among the PR cell lines. Compared to the PS counterparts, the PR PEO4, C200, and R182 lines had metabolite concentrations with FC≥1.5 in 29, 44, and 28 measured metabolites, respectively. The top pathways impacted were ‘nicotinate and nicotinamide metabolism’, ‘purine metabolism’, and ‘phenylalanine, tyrosine, tryptophan biosynthesis’. A global analysis of PS vs PR was performed. The top five significantly impacted pathways were: Arginine biosynthesis, Pyrimidine and Purine metabolism, Phenylalanine, tyrosine and tryptophan biosynthesis’ and ‘Starch and sucrose metabolism’.
Conclusions We identified multiple shared metabolomic pathways among established PR OC cell lines that highlight conserved motifs of PR. These may represent targetable pathways to predict or reverse chemoresistance.
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