Sirtuin 1 stimulates the proliferation and the expression of glycolysis genes in pancreatic neoplastic lesions.

Andreia V Pinho,Amanda Mawson,Nils Eling,Simone Camargo,Triyana Lie,Evelyne Kuster,Ilse Rooman,Max Warmerdam,Marc Giry-Laterriere,Anthony Gill,Jianmin Wu,Andrew V Biankin,Mehreen Arshi

doi:10.18632/oncotarget.11013

Abstract

Metabolic reprogramming is a feature of neoplasia and tumor growth. Sirtuin 1 (SIRT1) is a lysine deacetylase of multiple targets including metabolic regulators such as p53. SIRT1 regulates metaplasia in the pancreas. Nevertheless, it is unclear if SIRT1 affects the development of neoplastic lesions and whether metabolic gene expression is altered.To assess neoplastic lesion development, mice with a pancreas-specific loss of Sirt1 (Pdx1-Cre;Sirt1-lox) were bred into a KrasG12D mutant background (KC) that predisposes to the development of pancreatic intra-epithelial neoplasia (PanIN) and ductal adenocarcinoma (PDAC). Similar grade PanIN lesions developed in KC and KC;Sirt1-lox mice but specifically early mucinous PanINs occupied 40% less area in the KC;Sirt1-lox line, attributed to reduced proliferation. This was accompanied by reduced expression of proteins in the glycolysis pathway, such as GLUT1 and GAPDH.The stimulatory effect of SIRT1 on proliferation and glycolysis gene expression was confirmed in a human PDAC cell line. In resected PDAC samples, higher proliferation and expression of glycolysis genes correlated with poor patient survival. SIRT1 expression per se was not prognostic but low expression of Cell Cycle and Apoptosis Regulator 2 (CCAR2), a reported SIRT1 inhibitor, corresponded to poor patient survival.These findings open perspectives for novel targeted therapies in pancreatic cancer.

Highlights

The incidence of pancreatic cancer is on the rise, being projected to become the second cause of cancerrelated deaths by 2030 [1]
Sirt1 promotes the proliferation of mucinous intraepithelial neoplastic lesions in the murine pancreas
Mice with an activating mutation in Kras [15] that is targeted to the pancreas by a Pdx1-Cre driver were crossed with a mouse line in which the exon 4 of Sirt1 is flanked by loxP sites to obtain homozygous Sirt1-deficient KrasG12D mutant background (KC) mice (KC;Sirt1-lox) [14, 16]

Summary

Introduction

The incidence of pancreatic cancer is on the rise, being projected to become the second cause of cancerrelated deaths by 2030 [1]. Patients diagnosed with pancreatic ductal adenocarcinoma (PDAC), the most common form of pancreatic cancer, still face a very poor outcome with a 5-year survival of 5–7%. Surgical resection offers the best chance of cure; most patients present with locally advanced or metastatic disease and are ineligible for surgery [2]. Novel combination therapies such as nab-paclitaxel with gemcitabine or FOLFIRINOX have improved patient outcomes but improvements are small and toxicity is an issue [2]. Sirtuin (SIRT1) inhibitors have shown promising results in preclinical models of PDAC (reviewed in [3]). SIRT1 is an evolutionary conserved protein that senses www.impactjournals.com/oncotarget

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