TY - JOUR
T1 - KRAS-regulated glutamine metabolism requires UCP2-mediated aspartate transport to support pancreatic cancer growth.
AU - Raho, Susanna
AU - Capobianco, Loredana
AU - Malivindi, Rocco
AU - Vozza, Angelo
AU - Piazzolla, Carmela
AU - De Leonardis, Francesco
AU - Gorgoglione, Ruggiero
AU - Scarcia, Pasquale
AU - Pezzuto, Francesca
AU - Agrimi, Gennaro
AU - Barile, Simona N.
AU - Pisano, Isabella
AU - Reshkin, Stephan J.
AU - Greco, Maria R.
AU - Cardone, Rosa A.
AU - Rago, Vittoria
AU - Li, Yuan
AU - Marobbio, Carlo M.T.
AU - Sommergruber, Wolfgang
AU - Riley, Christopher L.
AU - Lasorsa, Francesco M.
AU - Mills, Edward
AU - Vegliante, Maria C.
AU - De Benedetto, Giuseppe E.
AU - Fratantonio, Deborah
AU - Palmieri, Luigi
AU - Dolce, Vincenza
AU - Fiermonte, Giuseppe
N1 - Funding Information:
This work was supported by a grant from the Italian Association for Cancer Research (AIRC no. IG 2014 Id.15404 to G.F.) and a grant from the Italian Ministero dell’Istruzione, dell’Università e della Ricerca (no. 2017PAB8EM_002 to G.F.).
Publisher Copyright:
© 2020, The Author(s), under exclusive licence to Springer Nature Limited.
PY - 2021/12
Y1 - 2021/12
N2 - 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.
AB - 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.
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U2 - 10.1038/s42255-020-00315-1
DO - 10.1038/s42255-020-00315-1
M3 - Article
C2 - 33230296
AN - SCOPUS:85096437904
SN - 2522-5812
VL - 2
SP - 1373
EP - 1381
JO - Nature Metabolism
JF - Nature Metabolism
IS - 12
ER -