Metabolic Characterization of Antifolate Responsiveness and Non-responsiveness in Malignant Pleural Mesothelioma Cells.

Yuzo Sato,Masaru Tomita,Katsuya Tsuchihara,Kazuyoshi Yanagihara,Atsushi Ochiai,Joji Nakayama,Ami Maruyama,Tomoyoshi Soga,Shigeki Umemura,Tomoyuki Miyashita,Shiori Matsuda,Hideki Makinoshima,Hibiki Udagawa

doi:10.3389/fphar.2018.01129

Abstract

Antifolates are a class of drugs effective for treating malignant pleural mesothelioma (MPM). The majority of antifolates inhibit enzymes involved in purine and pyrimidine synthesis such as dihydrofolate reductase (DHFR), thymidylate synthase (TYMS), and glycinamide ribonucleotide formyltransferase (GART). In order to select the most suitable patients for effective therapy with drugs targeting specific metabolic pathways, there is a need for better predictive metabolic biomarkers. Antifolates can alter global metabolic pathways in MPM cells, yet the metabolic profile of treated cells has not yet been clearly elucidated. Here we found that MPM cell lines could be categorized into two groups according to their sensitivity or resistance to pemetrexed treatment. We show that pemetrexed susceptibility could be reversed and DNA synthesis rescued in drug-treated cells by the exogenous addition of the nucleotide precursors hypoxanthine and thymidine (HT). We observed that the expression of pemetrexed-targeted enzymes in resistant MPM cells was quantitatively lower than that seen in pemetrexed-sensitive cells. Metabolomic analysis revealed that glycine and choline, which are involved in one-carbon metabolism, were altered after drug treatment in pemetrexed-sensitive but not resistant MPM cells. The addition of HT upregulated the concentration of inosine monophosphate (IMP) in pemetrexed-sensitive MPM cells, indicating that the nucleic acid biosynthesis pathway is important for predicting the efficacy of pemetrexed in MPM cells. Our data provide evidence that may link therapeutic response to the regulation of metabolism, and points to potential biomarkers for informing clinical decisions regarding the most effective therapies for patients with MPM.

Highlights

Malignant pleural mesothelioma is a locally invasive and rapidly fatal malignancy linked to asbestos exposure (Liu et al, 2017; Yap et al, 2017)
The addition of hypoxanthine and thymidine (HT) upregulated the concentration of inosine monophosphate (IMP) in pemetrexed-sensitive malignant pleural mesothelioma (MPM) cells, indicating that the nucleic acid biosynthesis pathway is important for predicting the efficacy of pemetrexed in MPM cells
We found that MPM cell lines could be categorized into two groups according to their susceptibility to pemetrexed treatment

Summary

INTRODUCTION

Malignant pleural mesothelioma is a locally invasive and rapidly fatal malignancy linked to asbestos exposure (Liu et al, 2017; Yap et al, 2017). One-carbon metabolism involving the folate and methionine cycle integrates carbon units from amino acids and generates diverse outputs, such as the biosynthesis of nucleotides, lipids and proteins in cancer cells (Yang and Vousden, 2016; Ducker and Rabinowitz, 2017; Newman and Maddocks, 2017). Given the high proliferation rate of cancer cells and the requirement of nucleotides for proliferation, cancer cells have a large demand for one-carbon units for nucleotide synthesis (Yang and Vousden, 2016; Ducker and Rabinowitz, 2017; Newman and Maddocks, 2017) To this day, chemical variants of these initial folate antagonists such as methotrexate and pemetrexed constitute a major class of cancer chemotherapy agents and are used as frontline chemotherapy for diverse cancers (Zhao and Goldman, 2003).

EXPERIMENTAL PROCEDURES

RESULTS

DISCUSSION