Paclitaxel resistance of ovarian clear cell carcinoma reveals the ABC- and SLC- transporter genes to mediate glycolytic metabolism.

Abstract Background Ovarian clear cell carcinoma (OCCC) often becomes resistant to platinum based therapy when at an advanced stage. However, metabolic phenotypes and changes in its resistance remain unclear. Hence, we investigated the metabolic effect of paclitaxel resistance in OCCC and normal ovarian epithelium OSE2a cells. Methods The viability and cytotoxicity of paclitaxel resistant cells were determined. Glycolytic stress was measured using a Seahorse extracellular flux analyzer. RNA sequencing (RNA-Seq) was used to elucidate differentially expressed genes upon paclitaxel resistance Comprehensive metabolomics (capillary electrophoresis time of flight mass spectrometry (CE-TOFMS and CE-QqQMS) and transcriptomics analysis (RNA-Seq) were performed to characterize metabolic pathways in paclitaxel resistant OCCC cells. Results ES2 resistant cells had slower ATP and guanosine 5' triphosphate (GTP inflow and a greater nicotinamide adenine dinucleotide (NADH/NADH coenzyme (NAD ratio with an elevated oxygen consumption rate. Sets of ABC binding cassette (ABC- and solute carrier (SLC) transporter genes were found to be enriched in ES2 resistant cells involving glycolysis metabolism and molecular transport. We further demonstrate d that in response to high paclitaxel resistance, characteristic metabolomic changes in ES2 cells were a reduction in the energy requiring phase of glycolysis and the induction of metabolites in the energy releasing phase of glycolysis . Moreover, metabolite levels of selected cancer related nonessential amino acids, including serine glycine metabolism increased with paclitaxel resistance. Conclusions This is the first work to elucidate metabolic profiles of paclitaxel resistance in OCCC cells, indicating possible underlying mechanisms by which cells respond to paclitaxel cells, indicating possible underlying mechanisms by which cells respond to paclitaxel therapy through therapy through ABC-- and SLC--transporter genes, thereby affecting glycolysis transporter genes, thereby affecting glycolysis metabolism metabolism inin response to paclitaxel resistance.response to paclitaxel resistance.