Sirtuin1 stimulates the proliferation and the expression of glycolysis genes in pancreatic neoplastic lesions

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

Research output: Contribution to journalArticleResearchpeer-review

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.

LanguageEnglish
Pages74768-74778
Number of pages11
JournalOncotarget
Volume7
Issue number46
DOIs
Publication statusPublished - 2016
Externally publishedYes

Fingerprint

Sirtuin 1
Glycolysis
Gene Expression
Adenocarcinoma
Pancreas
Neoplasms
Survival
Metaplasia
Pancreatic Neoplasms
Lysine
Cell Cycle
Apoptosis
Cell Line
Growth

Keywords

  • Glycolysis
  • Pancreatic ductal adenocarcinoma
  • Proliferation
  • Sirtuin 1
  • Tumorigenesis

Cite this

Pinho, A. V., Mawson, A., Gill, A., Arshi, M., Warmerdam, M., Giry-Laterriere, M., ... Rooman, I. (2016). Sirtuin1 stimulates the proliferation and the expression of glycolysis genes in pancreatic neoplastic lesions. Oncotarget, 7(46), 74768-74778. https://doi.org/10.18632/oncotarget.11013
Pinho, Andreia V. ; Mawson, Amanda ; Gill, Anthony ; Arshi, Mehreen ; Warmerdam, Max ; Giry-Laterriere, Marc ; Eling, Nils ; Lie, Triyana ; Kuster, Evelyne ; Camargo, Simone ; Biankin, Andrew V. ; Wu, Jianmin ; Rooman, Ilse. / Sirtuin1 stimulates the proliferation and the expression of glycolysis genes in pancreatic neoplastic lesions. In: Oncotarget. 2016 ; Vol. 7, No. 46. pp. 74768-74778.
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Pinho, AV, Mawson, A, Gill, A, Arshi, M, Warmerdam, M, Giry-Laterriere, M, Eling, N, Lie, T, Kuster, E, Camargo, S, Biankin, AV, Wu, J & Rooman, I 2016, 'Sirtuin1 stimulates the proliferation and the expression of glycolysis genes in pancreatic neoplastic lesions', Oncotarget, vol. 7, no. 46, pp. 74768-74778. https://doi.org/10.18632/oncotarget.11013

Sirtuin1 stimulates the proliferation and the expression of glycolysis genes in pancreatic neoplastic lesions. / Pinho, Andreia V.; Mawson, Amanda; Gill, Anthony; Arshi, Mehreen; Warmerdam, Max; Giry-Laterriere, Marc; Eling, Nils; Lie, Triyana; Kuster, Evelyne; Camargo, Simone; Biankin, Andrew V.; Wu, Jianmin; Rooman, Ilse.

In: Oncotarget, Vol. 7, No. 46, 2016, p. 74768-74778.

Research output: Contribution to journalArticleResearchpeer-review

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AU - Pinho, Andreia V.

AU - Mawson, Amanda

AU - Gill, Anthony

AU - Arshi, Mehreen

AU - Warmerdam, Max

AU - Giry-Laterriere, Marc

AU - Eling, Nils

AU - Lie, Triyana

AU - Kuster, Evelyne

AU - Camargo, Simone

AU - Biankin, Andrew V.

AU - Wu, Jianmin

AU - Rooman, Ilse

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