1. Academic Validation
  2. Loss of heterozygosity for KrasG12D promotes REDD1-dependent, non-canonical glutamine metabolism in pancreatic ductal adenocarcinoma

Loss of heterozygosity for KrasG12D promotes REDD1-dependent, non-canonical glutamine metabolism in pancreatic ductal adenocarcinoma

  • Biochem Biophys Res Commun. 2020 Jun 11;526(4):880-888. doi: 10.1016/j.bbrc.2020.03.137.
Yu Ma 1 Yuan Li 1 Sunkai Ling 1 Xiaoxue Li 1 Bo Kong 2 Mingyue Hu 3 Peilin Huang 4
Affiliations

Affiliations

  • 1 School of Medicine, Southeast University, Nanjing, 210009, China.
  • 2 Department of Surgery, Klinikumrechts der Isar, School of Medicine, Technical University of Munich (TUM), Munich, 81675, Germany.
  • 3 School of Medicine, Southeast University, Nanjing, 210009, China; Department of Gastroenterology, Southeast University, Dingjiaqiao 87, Gulou District, Nanjing, 210009, China. Electronic address: [email protected].
  • 4 School of Medicine, Southeast University, Nanjing, 210009, China. Electronic address: [email protected].
Abstract

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 KrasG12D (KrasG12D-LOH) frequently observed in PDAC is associated with an aggressive and invasive phenotype. However, it remains unclear whether KrasG12D-LOH contributes to non-canonical Gln metabolism in PDAC. Here, we showed that KrasG12D-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 KrasG12D-LOH PDAC, and that REDD1 knockdown efficiently repressed KrasG12D-LOH-regulated Gln metabolism and suppressed proliferation, migration, and invasion of KrasG12D-LOH PDAC cells. These data provide evidence that REDD1 is a downstream target of KrasG12D-LOH and is involved in promoting non-canonical Gln metabolism in PDAC.

Keywords

Kras(G12D); Loss of heterozygosity; Non-canonical glutamine metabolism; Pancreatic ductal adenocarcinoma; REDD1.

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