2. Academic Validation
  3. Metabolic Rewiring by Loss of Sirt5 Promotes Kras-Induced Pancreatic Cancer Progression

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

  • Gastroenterology. 2021 Nov;161(5):1584-1600. doi: 10.1053/j.gastro.2021.06.045.
Tuo Hu 1,  Surendra K Shukla 2,  Enza Vernucci 2,  Chunbo He 2,  Dezhen Wang 2,  Ryan J King 2,  Kanupriya Jha 3,  Kasturi Siddhanta 4,  Nicholas J Mullen 2,  Kuldeep S Attri 2,  Divya Murthy 2,  Nina V Chaika 2,  Ravi Thakur 2,  Scott E Mulder 4,  Camila G Pacheco 2,  Xiao Fu 2,  Robin R High 5,  Fang Yu 5,  Audrey Lazenby 6,  Clemens Steegborn 7,  Ping Lan 8,  Kamiya Mehla 2,  Dante Rotili 9,  Sarika Chaudhary 3,  Sergio Valente 9,  Marco Tafani 10,  Antonello Mai 9,  Johan Auwerx 11,  Eric Verdin 12,  David Tuveson 13,  Pankaj K Singh 14
Affiliations

Affiliations

  • 1 The Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, Nebraska; Department of Colorectal Surgery, Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China.
  • 2 The Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, Nebraska.
  • 3 Department of Biotechnology, School of Engineering and Applied Sciences, Bennett University, Greater Noida, Uttar Pradesh, India.
  • 4 The Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, Nebraska; Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, Nebraska.
  • 5 Department of Biostatistics, University of Nebraska Medical Center, Omaha, Nebraska.
  • 6 Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, Nebraska.
  • 7 University of Bayreuth, Department of Biochemistry, Bayreuth, Germany.
  • 8 Department of Colorectal Surgery, Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China.
  • 9 Department of Drug Chemistry and Technologies, Sapienza University of Rome, Rome, Italy.
  • 10 Department of Experimental Medicine, Sapienza University of Rome, Rome, Italy.
  • 11 Laboratory for Integrative Systems Physiology, Ecole Polytechnique Fédérale de Lausanne, Lausanne, Switzerland.
  • 12 Buck Institute for Research on Aging, Novato, California.
  • 13 Cancer Center at Cold Spring Harbor Laboratory, Cold Spring Harbor, New York.
  • 14 The Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, Nebraska; Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, Nebraska; Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, Nebraska; Fred & Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, Nebraska. Electronic address: Pankaj.singh@unmc.edu.
PMID: 34245764 DOI: 10.1053/j.gastro.2021.06.045
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 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.

Keywords

GOT1; Glutamine Metabolism; Glutathione Metabolism; Pancreatic Cancer; SIRT5.

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Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-160818
    SIRT5 Inhibitor