Loss of heterozygosity for Kras^G12D promotes REDD1-dependent, non-canonical glutamine metabolism in pancreatic ductal adenocarcinoma.

Pancreatic cancer is associated with high mortality, and pancreatic ductal adenocarcinoma (PDAC) is its most common subtype. The rapid growth of PDAC is dependent on the non-canonical pathway of glutamine (Gln) utilization, and loss of heterozygosity for Kras^G12D (Kras^G12D-LOH) frequently observed in PDAC is associated with an aggressive and invasive phenotype. However, it remains unclear whether Kras^G12D-LOH contributes to non-canonical Gln metabolism in PDAC. Here, we showed that Kras^G12D-LOH leads to a substantial increase in non-canonical Gln metabolism in PDAC cells. Importantly, we observed elevated expression of regulated in DNA damage and development 1 (REDD1), which is activated in response to hypoxia and nutrient deprivation, in Kras^G12D-LOH PDAC, and that REDD1 knockdown efficiently repressed Kras^G12D-LOH-regulated Gln metabolism and suppressed proliferation, migration, and invasion of Kras^G12D-LOH PDAC cells. These data provide evidence that REDD1 is a downstream target of Kras^G12D-LOH and is involved in promoting non-canonical Gln metabolism in PDAC.

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