KRAS-regulated glutamine metabolism requires UCP2-mediated aspartate transport to support pancreatic cancer growth.
Nat Metab
; 2(12): 1373-1381, 2020 12.
Article
en En
| MEDLINE
| ID: mdl-33230296
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.
Texto completo:
1
Colección:
01-internacional
Asunto principal:
Neoplasias Pancreáticas
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Proteínas Proto-Oncogénicas p21(ras)
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Ácido Aspártico
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Carcinoma Ductal Pancreático
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Proteína Desacopladora 2
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Glutamina
Límite:
Animals
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Female
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Humans
Idioma:
En
Revista:
Nat Metab
Año:
2020
Tipo del documento:
Article
País de afiliación:
Italia