Glutamine deficiency induces DNA alkylation damage and sensitizes cancer cells to alkylating agents through inhibition of ALKBH enzymes

• Published in: PLoS biology Vol. 15; no. 11; p. e2002810
• Main Authors: Tran, Thai Q., Ishak Gabra, Mari B., Lowman, Xazmin H., Yang, Ying, Reid, Michael A., Pan, Min, O’Connor, Timothy R., Kong, Mei
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 06.11.2017; Public Library of Science (PLoS)
• Subjects: Addiction; Addictions; AlkB Enzymes - antagonists & inhibitors; AlkB Enzymes - genetics; AlkB Enzymes - metabolism; AlkB Homolog 3, Alpha-Ketoglutarate-Dependent Dioxygenase - antagonists & inhibitors; AlkB Homolog 3, Alpha-Ketoglutarate-Dependent Dioxygenase - genetics; AlkB Homolog 3, Alpha-Ketoglutarate-Dependent Dioxygenase - metabolism; Alkylating agents; Alkylation; Alkylation - drug effects; Animals; Antineoplastic Agents, Alkylating - pharmacology; Antineoplastic Agents, Alkylating - therapeutic use; Antineoplastic Combined Chemotherapy Protocols - pharmacology; Antineoplastic Combined Chemotherapy Protocols - therapeutic use; Apoptosis - drug effects; Biology; Biology and Life Sciences; Cancer; Cancer cells; Cell death; Cell Line, Tumor; Cell Proliferation - drug effects; Crosstalk; Damage accumulation; Data collection; Deoxyribonucleic acid; Deprivation; DNA; DNA Damage; DNA methylation; DNA repair; Enzyme Inhibitors - pharmacology; Enzyme Inhibitors - therapeutic use; Enzymes; Genomic instability; Glucose; Glutaminase; Glutaminase - antagonists & inhibitors; Glutaminase - metabolism; Glutamine; Glutamine metabolism; Homology; Humans; Ketoglutaric acid; Male; Medicine and Health Sciences; Metabolism; Metabolites; Mice; Mice, Nude; Mutation; Neoplasm Proteins - antagonists & inhibitors; Neoplasm Proteins - genetics; Neoplasm Proteins - metabolism; Neoplasms - drug therapy; Neoplasms - metabolism; Neoplasms - pathology; Norleucine; Physical Sciences; Physiological aspects; Random Allocation; Research and Analysis Methods; RNA Interference; Signaling; Solid tumors; Stability; Tumor Burden - drug effects; Tumor cells; Tumors; Xenograft Model Antitumor Assays
• ISSN: 1545-7885; 1544-9173; 1545-7885
• DOI: 10.1371/journal.pbio.2002810

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.