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High SIRT1 expression is a negative prognosticator in pancreatic ductal adenocarcinoma

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

In: BMC Cancer, 13 (2013), Nr. 450. pp. 1-12. ISSN 1471-2407

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Download (1MB) | Lizenz: Creative Commons LizenzvertragHigh SIRT1 expression is a negative prognosticator in pancreatic ductal adenocarcinoma by 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 underlies the terms of Creative Commons Attribution 3.0 Germany

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Abstract

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.

Item Type: Article
Journal or Publication Title: BMC Cancer
Volume: 13
Number: 450
Publisher: BioMed Central; Springer
Place of Publication: London; Berlin; Heidelberg
Date Deposited: 07 Apr 2016 08:38
Date: 2013
ISSN: 1471-2407
Page Range: pp. 1-12
Faculties / Institutes: Medizinische Fakultät Heidelberg > Pathologisches Institut
Subjects: 610 Medical sciences Medicine
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