title: High SIRT1 expression is a negative prognosticator in pancreatic ductal adenocarcinoma
creator: Stenzinger, Albrecht
creator: Endris, Volker
creator: Klauschen, Frederick
creator: Sinn, Bruno
creator: Lorenz, Katja
creator: Warth, Arne
creator: Goeppert, Benjamin
creator: Ehemann, Volker
creator: Muckenhuber, Alexander
creator: Kamphues, Carsten
creator: Bahra, Marcus
creator: Neuhaus, Peter
creator: Weichert, Wilko
subject: 610
subject: 610 Medical sciences Medicine
description: Background: Several lines of evidence indicate that Sirt1, a class III histone deacetylase (HDAC) is implicated in the initiation and progression of malignancies and thus gained attraction as druggable target. Since data on the role of Sirt1 in pancreatic ductal adenocarcinoma (PDAC) are sparse, we investigated the expression profile and prognostic significance of Sirt1 in vivo as well as cellular effects of Sirt1 inhibition in vitro.   Methods: Sirt1 expression was analyzed by immunohistochemistry in a large cohort of PDACs and correlated with clinicopathological and survival data. Furthermore, we investigated the impact of overexpression and small molecule inhibition on Sirt1 in pancreatic cancer cell culture models including combinatorial treatment with chemotherapy and EGFR-inhibition. Cellular events were measured quantitatively in real time and corroborated by conventional readouts including FACS analysis and MTT assays.   Results: We detected nuclear Sirt1 expression in 36 (27.9%) of 129 PDACs. SIRT1 expression was significantly higher in poorly differentiated carcinomas. Strong SIRT1 expression was a significant predictor of poor survival both in univariate (p = 0.002) and multivariate (HR 1.65, p = 0.045) analysis. Accordingly, overexpression of Sirt1 led to increased cell viability, while small molecule inhibition led to a growth arrest in pancreatic cancer cells and impaired cell survival. This effect was even more pronounced in combinatorial regimens with gefitinib, but not in combination with gemcitabine.   Conclusions: Sirt1 is an independent prognosticator in PDACs and plays an important role in pancreatic cancer cell growth, which can be levered out by small molecule inhibition. Our data warrant further studies on SIRT1 as a novel chemotherapeutic target in PDAC.
publisher: BioMed Central; Springer
date: 2013
type: Article
type: info:eu-repo/semantics/article
type: NonPeerReviewed
format: application/pdf
identifier: https://archiv.ub.uni-heidelberg.de/volltextserverhttps://archiv.ub.uni-heidelberg.de/volltextserver/20473/1/12885_2013_Article_5259.pdf
identifier: DOI:
identifier: urn:nbn:de:bsz:16-heidok-204734
identifier:   Stenzinger, Albrecht ; Endris, Volker ; Klauschen, Frederick ; Sinn, Bruno ; Lorenz, Katja ; Warth, Arne ; Goeppert, Benjamin ; Ehemann, Volker ; Muckenhuber, Alexander ; Kamphues, Carsten ; Bahra, Marcus ; Neuhaus, Peter ; Weichert, Wilko  (2013) High SIRT1 expression is a negative prognosticator in pancreatic ductal adenocarcinoma.  BMC Cancer, 13 (450).  pp. 1-12.  ISSN 1471-2407     
relation: https://archiv.ub.uni-heidelberg.de/volltextserver/20473/
rights: info:eu-repo/semantics/openAccess
rights: Please see front page of the work (Sorry, Dublin Core plugin does not recognise license id)
language: eng