Targeted inhibition of glutaminase as a potential new approach for the treatment of NF1 associated soft tissue malignancies.

Tahir N Sheikh,Parag P Patwardhan,Gary K Schwartz,Serge Cremers

doi:10.18632/oncotarget.21573

Abstract

Many cancer cells rely on glutamine as the source of carbon molecules to feed the biosynthetic pathways and are often addicted to glutaminolysis. Inhibitors of glutaminase activity have gained attention in the last few years due to their anti-proliferative effect and ability to induce apoptosis in some cancers. Although it is a promising therapeutic approach, its efficacy or the role played by glutamine in modulating cell proliferation in NF1 associated tumors has never been studied. We report for the first time, a strong correlation between the NF1 status of tumor cells and increased sensitivity to glutamine deprivation and glutaminase inhibition. Soft-tissue cell lines null for NF1 were highly dependent on glutamine for proliferation and showed decreased mTORC1 and Ras activity in response to glutaminase inhibition. Re-addition of glutamine or intermediary metabolite such as glutamate to the media restored mTORC1 and Ras activity. SiRNA mediated NF1 knockdown in wild-type NF1 cell line shows increased sensitivity to glutaminase inhibition. Conversely, NF1 overexpression in NF1 null cell lines results in reduced sensitivity to glutaminase inhibition, and restores mTORC1 signaling and Ras activity. These findings provide new insights into the role played by glutamine metabolism in NF1 associated tumors and strongly warrant further investigation as a potential therapy in the NF1 disease setting.

Highlights

Normal cells produce energy mostly through the oxidation of pyruvate in the mitochondria; cancer cells are known to produce energy via increased glycolysis in the cytosol
We report for the first time that Neurofibromatosis type 1 (NF1) associated soft-tissue sarcoma cell lines (MPNST, ST8814, S462) are highly dependent on glutamine for proliferation compared to wild-type NF1 cell lines (LS141, CHP100, STS26T)
NF1 is known to play a role in the development of malignant peripheral nerve sheath tumors (MPNSTs), its role in modulating glutamine dependency has not been studied before

Summary

Introduction

Normal cells produce energy mostly through the oxidation of pyruvate in the mitochondria; cancer cells are known to produce energy via increased glycolysis in the cytosol. This effect known as “Warburg Effect” [1] requires a metabolic shift from oxidative phosphorylation to glycolysis or lactate fermentation [2]. As a result of glutamine being a major source of carbon molecules in tumor growth-facilitating metabolic pathways, many cancer cells often become “addicted” to glutaminolysis (a rate limiting step in the TCA cycle) [5]. Cancer cells addicted to glutaminolysis often rely on glutamine as the carbon source for the TCA cycle [8]

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Conclusion