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.
MeSH terms
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AlkB Enzymes / antagonists & inhibitors*
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AlkB Enzymes / genetics
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AlkB Enzymes / metabolism
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AlkB Homolog 3, Alpha-Ketoglutarate-Dependent Dioxygenase / antagonists & inhibitors
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AlkB Homolog 3, Alpha-Ketoglutarate-Dependent Dioxygenase / genetics
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AlkB Homolog 3, Alpha-Ketoglutarate-Dependent Dioxygenase / metabolism
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Alkylation / drug effects
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Animals
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Antineoplastic Agents, Alkylating / pharmacology
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Antineoplastic Agents, Alkylating / therapeutic use*
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Antineoplastic Combined Chemotherapy Protocols / pharmacology
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Antineoplastic Combined Chemotherapy Protocols / therapeutic use*
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Apoptosis / drug effects
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Cell Line, Tumor
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Cell Proliferation / drug effects
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DNA Damage
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Enzyme Inhibitors / pharmacology
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Enzyme Inhibitors / therapeutic use*
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Glutaminase / antagonists & inhibitors*
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Glutaminase / metabolism
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Humans
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Male
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Mice
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Mice, Nude
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Neoplasm Proteins / antagonists & inhibitors*
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Neoplasm Proteins / genetics
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Neoplasm Proteins / metabolism
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Neoplasms / drug therapy*
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Neoplasms / metabolism
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Neoplasms / pathology
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RNA Interference
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Random Allocation
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Tumor Burden / drug effects
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Xenograft Model Antitumor Assays
Substances
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Antineoplastic Agents, Alkylating
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Enzyme Inhibitors
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Neoplasm Proteins
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ALKBH3 protein, human
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AlkB Homolog 3, Alpha-Ketoglutarate-Dependent Dioxygenase
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AlkB Enzymes
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Glutaminase