Loss of SIRT5, a sirtuin, was associated with tumorigenesis in pancreatic ductal adenocarcinoma (PDAC), according to research findings published in Gastroenterology. These study results suggest activation of SIRT5 could represent a potentially effective therapeutic strategy for PDAC.
Sirtuins are comprised of nicotinamide adenine dinucleotide (NAD+)-dependent enzymes that possess deacetylase activity. Previous research has implicated this class of proteins in cancer progression, given their role in cancer cell metabolism regulation, the tumor microenvironment, and genome stability. In particular, the pleiotropic role of SIRT5 suggests mammalian sirtuin may be a tumor suppressor, though the function of SIRT5 in initiating and progressing PDAC is currently unknown.
Researchers sought to further elucidate the clinically relevant role of SIRT5 in PDAC by examining published datasets and tissue arrays with SIRT5 staining. Autochthonous mouse models were generated with conditional Sirt5 knockout to further quantify the role of SIRT5 in PDAC carcinogenesis.
The mechanistic role of SIRT5 in the carcinogenesis of PDAC was also explored via knockdown of SIRT5 in PDAC cell lines and organoids, in addition to metabolomics and proteomics studies. The researchers relied on a novel SIRT5 activator for therapeutic studies in both patient-derived xenografts and organoids. Pancreatic cancer tissues, derived from the PanIN and tumor progression studies, were provided by the University of Nebraska Medical Center Tissue Bank.
Expression of SIRT3, SIRT5, and SIRT6 levels were significantly reduced in PDAC tissues. Utilizing the autochthonous LSL-KrasG12D, LSL-Trp53R172H, and Pdx1-Cre (KPC) mouse models, the researchers found that levels of Sirt5 mRNA and proteins were significantly reduced in KPC pancreatic cancer tissues compared with normal age-matched pancreatic tissues. While SIRT5 knockdown enhanced proliferation of PDAC cells, overexpression of the protein inhibited growth of these cells.
The researchers also discovered that SIRT5 negatively regulated noncanonical glutamine metabolism through direct, post-translational modifications of glutamine via cytosolic aspartate aminotransferase (GOT1). Expression of SIRT5 also negatively regulated proliferation of tumor cells and was associated with a favorable prognosis in patients with PDAC.
However, deletion of Sirt5 was associated with a significant promotion of pancreatic cancer cell proliferation, and loss of Sirt5 in KPC mice was associated with a significant reduction in survival. “Therefore, Sirt5 deletion, in cooperation with Kras and Tp53 mutations, accelerates pancreatic cancer progression and shortens the survival time of the spontaneous PDAC progression mouse model,” the study author’s commented.
From a mechanistic point of view, loss of SIRT5 enhanced glutamine and glutathione metabolism through acetylation-mediated GOT1 activation.
The researchers also evaluated the role of Sirt5 in KrasG12D-triggered pancreatic tumorigenesis in the pancreata of 4-month-old KCS mice. This was studied in the absence of caerulein, a cholecystokinin analog used to cause pancreatitis in experimental animal models. Ultimately, the researchers found that loss of Sirt5 also led to the oncogenic, KrasG12D-driven initiation of tumorigenesis in the mouse pancreas in the absence of caerulein.
MC3138, a 1,4-dihydropyridine selective activator of SIRT5, demonstrated anti-tumor effects on the human PDAC cell lines. While SIRT5 loss mediated an increase in pyrimidine nucleotide pools, MC3138 reduced nucleotide pools while sensitizing organoids, human PDAC cell lines, and patient-derived xenografts to the chemotherapy agent gemcitabine.
A limitation of this study was the reliance on PDAC cell lines, human tissue samples, and genetically-engineered mice. As such, the researchers suggest more work is needed in actual human patients.
Based on the findings, the researchers indicate SIRT5 activation with small-molecule SIRT5-activator MC3138, in combination with gemcitabine, may result in the development of a novel safe and effective therapy option for patients with PDAC and low tumoral SIRT5 expression.
Hu T, Shukla SK, Vernucci E, et al. Metabolic rewiring by loss of Sirt5 promotes Kras-induced pancreatic cancer progression. Published online July 7, 2021. Gastroenterol. doi:10.1053/j.gastro.2021.06.045