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.
journal_name
PLoS Bioljournal_title
PLoS biologyauthors
Tran TQ,Ishak Gabra MB,Lowman XH,Yang Y,Reid MA,Pan M,O'Connor TR,Kong Mdoi
10.1371/journal.pbio.2002810subject
Has Abstractpub_date
2017-11-06 00:00:00pages
e2002810issue
11eissn
1544-9173issn
1545-7885pii
pbio.2002810journal_volume
15pub_type
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