# GPT2 mediates metabolic alterations in platinum-resistant ovarian cancer cells

## TL;DR

This study shows that GPT2 enzyme drives metabolic changes in platinum-resistant ovarian cancer cells, contributing to drug resistance and poor patient outcomes.

## Contribution

The study identifies GPT2 as a novel metabolic driver of platinum resistance in ovarian cancer cells.

## Key findings

- Platinum-resistant ovarian cancer cells show increased oxidative phosphorylation and glutaminolysis.
- GPT2 gene expression is elevated in resistant cells and linked to worse patient prognosis.
- GPT2 knockout reverses metabolic changes and drug resistance in resistant cells.

## Abstract

Metabolic reprogramming is recognized as a hallmark of cancer frequently associated with drug resistance in ovarian cancer. This is problematic as ovarian cancer is one of the deadliest gynecologic cancers with platinum resistance contributing to poor survival. However, the mechanism by which ovarian cancer cell metabolism contributes to platinum resistance is not well understood. Herein, metabolic signatures were determined in platinum-resistant ovarian cancer cell lines compared to the more platinum-sensitive parental lines. Chemoresistant ovarian cancer cells showed increased oxidative phosphorylation (OXPHOS) compared to chemosensitive cells. This was associated with elevated levels of glutaminolysis and tricarboxylic acid (TCA)-related metabolites supporting their dependence on OXPHOS. Key enzymes involved in glutaminolysis, specifically, glutamic-pyruvic transaminase 2 (GPT2), were upregulated in chemoresistant compared to chemosensitive cells. Interestingly, high GPT2 gene expression is associated with worse prognosis in ovarian cancer patients, adding translational relevance to the pre-clinical findings. GPT2 knockout in chemoresistant cells restored the metabolic phenotype to that of the sensitive cells and reversed drug resistance. These data suggest that GPT2 is a critical link between glutaminolysis, the TCA cycle, and OXPHOS and is a potential target to attenuate the increased metabolic activity associated with a chemoresistant phenotype.