Abstract

Driven by oncogenic signaling, glutamine addiction exhibited by cancer cells often leads to severe glutamine depletion in solid tumors. Despite this nutritional environment that tumor cells often experience, the effect of glutamine deficiency on cellular responses to DNA damage and chemotherapeutic treatment remains unclear. Here, we show that glutamine deficiency, through the reduction of alpha-ketoglutarate, inhibits the AlkB homolog (ALKBH) enzymes activity and induces DNA alkylation damage. As a result, glutamine deprivation or glutaminase inhibitor treatment triggers DNA damage accumulation independent of cell death. In addition, low glutamine-induced DNA damage is abolished in ALKBH deficient cells. Importantly, we show that glutaminase inhibitors, 6-Diazo-5-oxo-L-norleucine (DON) or CB-839, hypersensitize cancer cells to alkylating agents both in vitro and in vivo. Together, the crosstalk between glutamine metabolism and the DNA repair pathway identified in this study highlights a potential role of metabolic stress in genomic instability and therapeutic response in cancer.

Highlights

  • Metabolic alterations exhibited by cancer cells can potentiate tumorigenesis and promote cell survival [1,2]

  • We found that glutamine deficiency inhibits the AlkB homolog (ALKBH) enzymes from repairing DNA alkylation damage, leading to DNA damage in the absence of the genotoxic agent

  • Mouse embryonic fibroblast (MEF) cells and prostate cancer PC3 cells were cultured in complete or glutamine free medium for 24 hours followed by immunofluorescence for γH2AX, an established biomarker for DNA damage [28]

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Summary

Introduction

Metabolic alterations exhibited by cancer cells can potentiate tumorigenesis and promote cell survival [1,2]. Cancer cells favor aerobic glycolysis, known as the Warburg effect, to support rapid proliferation [3]. Glutamine metabolism supports rapidly proliferating cells by facilitating the biosynthesis of different amino acids and nucleotides [3,5]. Glutamine supports the increased energetic demand and suppresses accumulated reactive oxygen species (ROS) exhibited in cancer cells [6]. The amino acid drives the production of glutathione (GSH), a major antioxidant, to protect cancer cells from ROS accumulation [9]. Inhibition of glutamine metabolism with small molecule inhibitors results in an energetic crisis leading to cellular death in some cancers [10,11]

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