Metabolic Rewiring by Loss of Sirt5 Promotes Kras-Induced Pancreatic Cancer Progression.
Animals
Antineoplastic Combined Chemotherapy Protocols
/ pharmacology
Aspartate Aminotransferase, Cytoplasmic
/ genetics
Carcinoma, Pancreatic Ductal
/ drug therapy
Cell Line, Tumor
Deoxycytidine
/ analogs & derivatives
Disease Progression
Energy Metabolism
/ drug effects
Enzyme Activation
Enzyme Activators
/ pharmacology
Female
Gene Expression Regulation, Neoplastic
Humans
Male
Mice, Inbred C57BL
Mice, Inbred NOD
Mice, Knockout
Mice, SCID
Mutation
Pancreatic Neoplasms
/ drug therapy
Proto-Oncogene Proteins p21(ras)
/ genetics
Signal Transduction
Sirtuins
/ deficiency
Tumor Burden
Tumor Cells, Cultured
Xenograft Model Antitumor Assays
Gemcitabine
GOT1
Glutamine Metabolism
Glutathione Metabolism
Pancreatic Cancer
SIRT5
Journal
Gastroenterology
ISSN: 1528-0012
Titre abrégé: Gastroenterology
Pays: United States
ID NLM: 0374630
Informations de publication
Date de publication:
11 2021
11 2021
Historique:
received:
21
01
2021
revised:
09
06
2021
accepted:
13
06
2021
pubmed:
11
7
2021
medline:
18
1
2022
entrez:
10
7
2021
Statut:
ppublish
Résumé
SIRT5 plays pleiotropic roles via post-translational modifications, serving as a tumor suppressor, or an oncogene, in different tumors. However, the role SIRT5 plays in the initiation and progression of pancreatic ductal adenocarcinoma (PDAC) remains unknown. Published datasets and tissue arrays with SIRT5 staining were used to investigate the clinical relevance of SIRT5 in PDAC. Furthermore, to define the role of SIRT5 in the carcinogenesis of PDAC, we generated autochthonous mouse models with conditional Sirt5 knockout. Moreover, to examine the mechanistic role of SIRT5 in PDAC carcinogenesis, SIRT5 was knocked down in PDAC cell lines and organoids, followed by metabolomics and proteomics studies. A novel SIRT5 activator was used for therapeutic studies in organoids and patient-derived xenografts. SIRT5 expression negatively regulated tumor cell proliferation and correlated with a favorable prognosis in patients with PDAC. Genetic ablation of Sirt5 in PDAC mouse models promoted acinar-to-ductal metaplasia, precursor lesions, and pancreatic tumorigenesis, resulting in poor survival. Mechanistically, SIRT5 loss enhanced glutamine and glutathione metabolism via acetylation-mediated activation of GOT1. A selective SIRT5 activator, MC3138, phenocopied the effects of SIRT5 overexpression and exhibited antitumor effects on human PDAC cells. MC3138 also diminished nucleotide pools, sensitizing human PDAC cell lines, organoids, and patient-derived xenografts to gemcitabine. Collectively, we identify SIRT5 as a key tumor suppressor in PDAC, whose loss promotes tumorigenesis through increased noncanonic use of glutamine via GOT1, and that SIRT5 activation is a novel therapeutic strategy to target PDAC.
Sections du résumé
BACKGROUND & AIMS
SIRT5 plays pleiotropic roles via post-translational modifications, serving as a tumor suppressor, or an oncogene, in different tumors. However, the role SIRT5 plays in the initiation and progression of pancreatic ductal adenocarcinoma (PDAC) remains unknown.
METHODS
Published datasets and tissue arrays with SIRT5 staining were used to investigate the clinical relevance of SIRT5 in PDAC. Furthermore, to define the role of SIRT5 in the carcinogenesis of PDAC, we generated autochthonous mouse models with conditional Sirt5 knockout. Moreover, to examine the mechanistic role of SIRT5 in PDAC carcinogenesis, SIRT5 was knocked down in PDAC cell lines and organoids, followed by metabolomics and proteomics studies. A novel SIRT5 activator was used for therapeutic studies in organoids and patient-derived xenografts.
RESULTS
SIRT5 expression negatively regulated tumor cell proliferation and correlated with a favorable prognosis in patients with PDAC. Genetic ablation of Sirt5 in PDAC mouse models promoted acinar-to-ductal metaplasia, precursor lesions, and pancreatic tumorigenesis, resulting in poor survival. Mechanistically, SIRT5 loss enhanced glutamine and glutathione metabolism via acetylation-mediated activation of GOT1. A selective SIRT5 activator, MC3138, phenocopied the effects of SIRT5 overexpression and exhibited antitumor effects on human PDAC cells. MC3138 also diminished nucleotide pools, sensitizing human PDAC cell lines, organoids, and patient-derived xenografts to gemcitabine.
CONCLUSIONS
Collectively, we identify SIRT5 as a key tumor suppressor in PDAC, whose loss promotes tumorigenesis through increased noncanonic use of glutamine via GOT1, and that SIRT5 activation is a novel therapeutic strategy to target PDAC.
Identifiants
pubmed: 34245764
pii: S0016-5085(21)03159-0
doi: 10.1053/j.gastro.2021.06.045
pmc: PMC8546779
mid: NIHMS1722572
pii:
doi:
Substances chimiques
Enzyme Activators
0
KRAS protein, human
0
SIRT5 protein, mouse
0
Deoxycytidine
0W860991D6
Aspartate Aminotransferase, Cytoplasmic
EC 2.6.1.-
GOT1 protein, human
EC 2.6.1.-
Got1 protein, mouse
EC 2.6.1.-
SIRT5 protein, human
EC 3.5.1.-
Sirtuins
EC 3.5.1.-
Hras protein, mouse
EC 3.6.5.2
Proto-Oncogene Proteins p21(ras)
EC 3.6.5.2
Gemcitabine
0
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
1584-1600Subventions
Organisme : NCI NIH HHS
ID : R01 CA216853
Pays : United States
Organisme : NCI NIH HHS
ID : P50 CA127297
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA163649
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA210439
Pays : United States
Organisme : NCI NIH HHS
ID : T32 CA009476
Pays : United States
Organisme : NCI NIH HHS
ID : P01 CA217798
Pays : United States
Commentaires et corrections
Type : CommentIn
Informations de copyright
Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.
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