Metabolic Rewiring by Loss of Sirt5 Promotes Kras-induced Pancreatic Cancer Progression.

Hu, Tuo, Shukla, Surendra K, Vernucci, Enza, He, Chunbo, Wang, Dezhen, King, Ryan J, Jha, Kanupriya, Siddhanta, Kasturi, Mullen, Nicholas J, Attri, Kuldeep S, Murthy, Divya, Chaika, Nina V, Thakur, Ravi, Mulder, Scott E, Pacheco, Camila G, Fu, Xiao, High, Robin R, Yu, Fang, Lazenby, Audrey, Steegborn, Clemens, Lan, Ping, Mehla, Kamiya, Rotili, Dante, Chaudhary, Sarika, Valente, Sergio, Tafani, Marco, Mai, Antonello, Auwerx, Johan, Verdin, Eric, Tuveson, David, Singh, Pankaj K (July 2021) Metabolic Rewiring by Loss of Sirt5 Promotes Kras-induced Pancreatic Cancer Progression. Gastroenterology. ISSN 0016-5085

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Abstract

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 utilized for therapeutic studies in organoids and patient-derived xenografts. RESULTS: SIRT5 expression negatively regulated tumor cell proliferation and correlated with a favorable prognosis in PDAC patients. 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 anti-tumor 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 non-canonical utilization of glutamine via GOT1, and that SIRT5 activation is a novel therapeutic strategy to target PDAC.

Item Type:	Paper
Subjects:	diseases & disorders > cancer diseases & disorders diseases & disorders > neoplasms organism description > animal organs, tissues, organelles, cell types and functions > cell types and functions > cell types > cell line organs, tissues, organelles, cell types and functions > cell types and functions > cell types > cell line organs, tissues, organelles, cell types and functions > cell types and functions > cell types > cell line organs, tissues, organelles, cell types and functions > cell types and functions > cell types organs, tissues, organelles, cell types and functions > cell types and functions > cell types organs, tissues, organelles, cell types and functions > cell types and functions > cell types organs, tissues, organelles, cell types and functions > cell types and functions diseases & disorders > cancer > drugs and therapies > chemotherapy diseases & disorders > cancer > drugs and therapies organism description > animal > mammal organs, tissues, organelles, cell types and functions > organs types and functions > metabolism organism description > animal > mammal > rodent > mouse organs, tissues, organelles, cell types and functions diseases & disorders > cancer > cancer types > pancreatic cancer organism description > animal > mammal > rodent organs, tissues, organelles, cell types and functions > tissues types and functions > signal transduction organs, tissues, organelles, cell types and functions > tissues types and functions
CSHL Authors:	Tuveson, David A.
Communities:	CSHL labs > Tuveson lab
SWORD Depositor:	CSHL Elements
Depositing User:	CSHL Elements
Date:	7 July 2021
Date Deposited:	12 Jul 2021 18:06
Last Modified:	24 Jan 2024 21:01
PMCID:	PMC8546779
URI:	https://repository.cshl.edu/id/eprint/40272

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