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

Author

Raho S, Capobianco L, Malivindi R, Vozza A, Piazzolla C, De Leonardis F, Gorgoglione R, Scarcia P, Pezzuto F, Agrimi G, Barile SN, Pisano I, Reshkin SJ, Greco MR, Cardone RA, Rago V, Li Y, Marobbio CMT, Sommergruber W, Riley CL, Lasorsa FM, Mills E, Vegliante MC, De Benedetto GE, Fratantonio D, Palmieri L, Dolce V, and Fiermonte G

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

Published
2020
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2. KRAS-regulated glutamine metabolism requires UCP2-mediated aspartate transport to support pancreatic cancer growth

Author

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

Subjects
endocrine system diseases, Endocrinology, Diabetes and Metabolism, Glutamine, Biological Transport, Active, Mice, SCID, Mitochondrion, Proto-Oncogene Proteins p21(ras), chemistry.chemical_compound, Mice, Cytosol, Physiology (medical), Cell Line, Tumor, Internal Medicine, Animals, Humans, Uncoupling Protein 2, oncogenic Kras, mitochondrial carrier, UCP2, human pancreatic ductal adenocarcinoma (PDAC), chemistry.chemical_classification, Reactive oxygen species, Aspartic Acid, Glutaminolysis, Cell growth, Animal, Pancreatic Neoplasm, Cell Biology, Xenograft Model Antitumor Assays, Cell biology, Mitochondria, Pancreatic Neoplasms, chemistry, Glutathione disulfide, Female, Aspartate transport, Reactive Oxygen Species, Reactive Oxygen Specie, Oxidation-Reduction, NADP, Carcinoma, Pancreatic Ductal, Human
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. 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.

Published
2020

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