SIRT1 overexpression in pancreatic adenocarcinomas correlates with shortened patient survival and small molecule inhibition as well as target knockdown of SIRT1 induces growth arrest and apoptosis in pancreatic cancer cells

作者:Stenzinger, A (Stenzinger, Albrecht)[ 1 ] ; Goppert, B (Goppert, Benjamin)[ 1 ] ; Kamphues, C (Kamphues, Carsten)[ 2 ] ; Sinn, B (Sinn, Bruno)[ 3 ] ; Bahra, M (Bahra, Markus)[ 2 ] ; Neuhaus, P (Neuhaus, Peter)[ 2 ] ; Weichert, W (Weichert, Wilko)[ 1 ]

CANCER RESEARCH

卷: 71

增刊: 8

会议摘要: 1624

DOI: 10.1158/1538-7445.AM2011-1624

出版年: APR 15 2011
Aims: Several lines of evidence indicate that the nuclear enzyme SIRT1 belonging to the class III histone deacetylases is implicated in the initiation and progression of various malignancies. SIRT1 exerts its function by regulating deacetylation of histone and non-histone substrates leading to transcriptional repression of tumor suppressor genes. Recently, SIRT1 gained attraction as druggable target. Since chemotherapeutic treatment options are still very limited in pancreatic cancer we aimed at investigating the potential of SIRT1 in this regard by evaluating the effects of SIRT1 inhibition in vitro and SIRT1 expression in vivo.

Proceedings: AACR 102nd Annual Meeting 2011‐‐ Apr 2‐6, 2011; Orlando, FL


Abstract

Aims: Several lines of evidence indicate that the nuclear enzyme SIRT1 belonging to the class III histone deacetylases is implicated in the initiation and progression of various malignancies. SIRT1 exerts its function by regulating deacetylation of histone and non-histone substrates leading to transcriptional repression of tumor suppressor genes. Recently, SIRT1 gained attraction as druggable target. Since chemotherapeutic treatment options are still very limited in pancreatic cancer we aimed at investigating the potential of SIRT1 in this regard by evaluating the effects of SIRT1 inhibition in vitro and SIRT1 expression in vivo.

Methods: Employing immunohistochemistry SIRT1 expression was analyzed in a large cohort of pancreatic ductal adenocarcinomas and subsequently correlated with clinicopathological data and patient survival. Furthermore, we investigated the impact of SIRT1-specific small molecule inhibition and target knock down as well as combinatorial regimens including conventional chemotherapy and small molecule inhibitors directed against the EGFR in pancreatic cancer cell culture models. Using the xCELLigence system, cellular events were measured quantitatively in real time and corroborated by secondary conventional readouts including FACS analysis.

Results: We found nuclear SIRT1 expression in 36 (27.9%) of 129 pancreatic carcinomas. SIRT1 expression was significantly higher in poorly differentiated carcinomas (p=0.002). SIRT1 expression was positively correlated with the expression of conventional HDACs suggesting a shared regulation. 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 under inclusion of WHO stage and grade.

Small molecule inhibition and target knockdown of SIRT1 lead to a rapid growth arrest and influenced cell viability. This effect was even more pronounced in combinatorial regimens with Gefitinib, but not in combination with Gemcitabine.

Conclusions: SIRT1 is shown to be an independent prognostic biomarker for pancreatic adenocarcinomas. Moreover our data suggest that SIRT1 plays an important functional role in pancreatic cancer cell growth, which can be levered out by combinatory small molecule inhibition.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1624. doi:10.1158/1538-7445.AM2011-1624，