Paclitaxel-resistance facilitates glycolytic metabolism via Hexokinase-2-regulated ABC and SLC transporter genes in ovarian clear cell carcinoma

Abstract

Ovarian clear cell carcinoma (OCCC) frequently develops resistance to platinum-based therapies, which is regarded as an aggressive subtype. However, metabolic changes in paclitaxel resistance remain unclear. Herein, we present the metabolic alternations of paclitaxel resistance in bioenergetic profiling in OCCC. Paclitaxel-resistant OCCC cells were developed and metabolically active with oxygen consumption rates (OCR) compared to parental cells. Metabolite profiling analysis revealed that paclitaxel-resistant OCCC cells reduced intracellular ATP and GTP influx rates, increasing the NADH/NAD+ ratio. We further demonstrated that paclitaxel-resistant OCCC cells led to characteristic alternations of metabolite levels in energy-requiring and energy-releasing steps of glycolysis and their corresponding glycolytic enzymes. Copy number alterations and RNA sequencing analysis demonstrated that ATP-binding cassette (ABC) transporters and solute carrier (SLC) transporter genes involved in glycolysis metabolism and molecular transport were enriched in paclitaxel-resistant OCCC cells. We first identified that Hexokinase 2 (HK2) expression is upregulated in paclitaxel-resistant OCCC cells to determine the quantity of glucose entering glycolysis. Utilizing proteolysis-targeting chimera (PROTAC) HK2 degraders, we also found that paclitaxel sensitivity, viability, and oxygen consumption rates under paclitaxel treatment were restored by HK2 degraders treatment, and decreased downstream expression of the ABC and SLC transporters was shown in OCCC cells. Taken together, these findings highlight the paclitaxel resistance in OCCC elucidates metabolic alternation, including ABC- and SLC- drug transporters, thereby affecting glycolysis metabolism in response to paclitaxel resistance, and HK2 may become a novel potential therapeutic target for paclitaxel resistance.