KRAS-regulated glutamine metabolism requires UCP2-mediated aspartate transport to support pancreatic cancer growth.

Abstract

The oncogenic KRAS mutation has a critical role in the initiation of human pancreatic ductal adenocarcinoma (PDAC) since it rewires glutamine metabolism to increase reduced nicotinamide adenine dinucleotide phosphate (NADPH) production, balancing cellular redox homeostasis with macromolecular synthesis1,2. Mitochondrial glutamine-derived aspartate must be transported into the cytosol to generate metabolic precursors for NADPH production2. The mitochondrial transporter responsible for this aspartate efflux has remained elusive. Here, we show that mitochondrial uncoupling protein 2 (UCP2) catalyses this transport and promotes tumour growth. UCP2-silenced KRASmut cell lines display decreased glutaminolysis, lower NADPH/NADP+ and glutathione/glutathione disulfide ratios and higher reactive oxygen species levels compared to wild-type counterparts. UCP2 silencing reduces glutaminolysis also in KRASWT PDAC cells but does not affect their redox homeostasis or proliferation rates. In vitro and in vivo, UCP2 silencing strongly suppresses KRASmut PDAC cell growth. Collectively, these results demonstrate that UCP2 plays a vital role in PDAC, since its aspartate transport activity connects the mitochondrial and cytosolic reactions necessary for KRASmut rewired glutamine metabolism2, and thus it should be considered a key metabolic target for the treatment of this refractory tumour.

• Authors: Susanna Raho, Loredana Capobianco, Rocco Malivindi, Angelo Vozza, Carmela Piazzolla, Francesco De Leonardis, Ruggiero Gorgoglione, Pasquale Scarcia, Francesca Pezzuto, Gennaro Agrimi, Simona N Barile, Isabella Pisano, Stephan J Reshkin, Maria R Greco, Rosa A Cardone, Vittoria Rago, Yuan Li, Carlo M T Marobbio, Wolfgang Sommergruber, Christopher L Riley, Francesco M Lasorsa, Edward Mills, Maria C Vegliante, Giuseppe E De Benedetto, Deborah Fratantonio, Luigi Palmieri, Vincenza Dolce, Giuseppe Fiermonte
• Journal: Nature metabolism (Nat Metab) Vol. 2 Issue 12 Pg. 1373-1381 (12 2020) ISSN: 2522-5812 [Electronic] Germany
• PMID: 33230296 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• KRAS protein, human
• Reactive Oxygen Species
• UCP2 protein, human
• Uncoupling Protein 2
• Glutamine
• Aspartic Acid
• NADP
• Proto-Oncogene Proteins p21(ras)

Topics

• Animals
• Aspartic Acid (metabolism)
• Biological Transport, Active
• Carcinoma, Pancreatic Ductal (metabolism)
• Cell Line, Tumor
• Cytosol (metabolism)
• Female
• Glutamine (metabolism)
• Humans
• Mice
• Mice, SCID
• Mitochondria (metabolism)
• NADP (metabolism)
• Oxidation-Reduction
• Pancreatic Neoplasms (metabolism)
• Proto-Oncogene Proteins p21(ras) (metabolism)
• Reactive Oxygen Species (metabolism)
• Uncoupling Protein 2 (metabolism)
• Xenograft Model Antitumor Assays