PDAC cells depend on a noncanonical glutamine metabolism pathway for redox homeostasis.
Major finding: PDAC cells depend on a noncanonical glutamine metabolism pathway for redox homeostasis.
Mechanism: Oncogenic KRAS upregulates aspartate transaminase and suppresses glutamate dehydrogenase.
Impact: Inhibition of glutamine metabolism may synergize with PDAC treatments that cause oxidative stress.
Due to their increased anabolic demands, some tumors have been shown to have an increased dependency on the amino acid glutamine, which provides carbon and nitrogen to biosynthetic pathways, but it is unclear if pancreatic ductal adenocarcinoma (PDAC), a highly lethal cancer without effective therapies, is similarly addicted to glutamine. Son and colleagues observed that PDAC cells were indeed highly sensitive to glutamine deprivation or inhibition of glutaminase, which converts glutamine to glutamate. However, unlike most cells, which are dependent on glutamate dehydrogenase (GLUD1)–mediated conversion of glutamate to α-ketoglutarate in the mitochondria, knockdown of GLUD1 had no effect on PDAC cells and α-ketoglutarate did not rescue growth following glutamine deprivation. Instead, in PDAC cells, oncogenic KRAS led to transcriptional repression of GLUD1 and activation of aspartate transaminase (GOT1), encoding a cytoplasmic component of a noncanonical glutamine metabolism pathway that converts glutamate-derived aspartate and α-ketoglutarate into oxaloacetate and glutamate. GOT1 knockdown significantly inhibited PDAC growth and increased reactive oxygen species (ROS) levels, suggesting that KRAS activates this alternative pathway to maintain redox homeostasis in PDAC cells. Consistent with this possibility, antioxidants rescued the growth inhibitory effects of glutamine deprivation, and metabolic tracing showed that glutamine-derived oxaloacetate is ultimately converted into the reducing agent NADPH. Knockdown of the enzymes in this noncanonical pathway had little effect on normal cells but significantly blocked PDAC growth in vivo, indicating that there may be a therapeutic window to inhibit this pathway. Moreover, inhibition of glutamine metabolism sensitized PDAC cells to oxidative stress. These findings raise the possibility that inhibitors of KRAS-regulated glutamine metabolism might potentiate the effects of ROS-generating treatments such as chemotherapy and radiation in PDAC.
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