Journal Article

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

Vegliante, Maria C., Lasorsa, Francesco M., Mills, Edward, De Leonardis, Francesco, De Benedetto, Giuseppe E., Greco, Maria R., Vozza, Angelo, Fratantonio, Deborah, Piazzolla, Carmela, Pezzuto, Francesca, Marobbio, Carlo M. T., Capobianco, Loredana, Fiermonte, Giuseppe, Pisano, Isabella, Cardone, Rosa A., Malivindi, Rocco, Scarcia, Pasquale, Rago, Vittoria, Sommergruber, Wolfgang, Gorgoglione, Ruggiero, Li, Yuan, Dolce, Vincenza, Agrimi, Gennaro, Riley, Christopher L., Raho, Susanna, Reshkin, Stephan J., Palmieri, Luigi, Barile, Simona N.

2020

Overview

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 synthesis 1 , 2 . Mitochondrial glutamine-derived aspartate must be transported into the cytosol to generate metabolic precursors for NADPH production 2 . 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 KRAS mut 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 KRAS WT PDAC cells but does not affect their redox homeostasis or proliferation rates. In vitro and in vivo, UCP2 silencing strongly suppresses KRAS mut 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 KRAS mut rewired glutamine metabolism 2 , and thus it should be considered a key metabolic target for the treatment of this refractory tumour. UCP2 is shown in yeast and mammalian cells to transport aspartate out of mitochondria, thus enabling KRAS -mutated pancreatic ductal adenocarcinoma cells to perform glutaminolysis to support cancer growth.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: 631/67/2327 / 631/80/313/2380 / Adenocarcinoma / Animals / Aspartic Acid - metabolism / Biological Transport, Active / Biomedical and Life Sciences / Carcinoma, Pancreatic Ductal - metabolism / Cell growth / Cell Line, Tumor / Cell proliferation / Cytosol / Cytosol - metabolism / Dehydrogenases / Female / Genes / Glutamine / Glutamine - metabolism / Glutathione / Homeostasis / Humans / K-Ras protein / Letter / Life Sciences / Mammalian cells / Metabolism / Metabolites / Mice / Mice, SCID / Mitochondria / Mitochondria - metabolism / Mitochondrial uncoupling protein 2 / NADP - metabolism / NADPH-diaphorase / Oxidation / Oxidation-Reduction / Pancreatic cancer / Pancreatic Neoplasms - metabolism / Proteins / Proto-Oncogene Proteins p21(ras) - metabolism / Reactive oxygen species / Reactive Oxygen Species - metabolism / Tumor cell lines / Tumors / Uncoupling Protein 2 - metabolism / Xenograft Model Antitumor Assays / Yeast