Downregulation of nuclear factor-κB p65 subunit by small interfering RNA synergizes with gemcitabine to inhibit the growth of pancreatic cancer

Kong, Rui; Sun, Bei; Jiang, Hongchi; Pan, Shangha; Chen, Hua; Wang, Shuangjia; Krissansen, Geoffrey W.; Sun, Xueying

doi:10.1016/j.canlet.2009.10.001

« Previous Next »Cancer Letters
Volume 291, Issue 1 , Pages 90-98, 1 May 2010

Downregulation of nuclear factor-κB p65 subunit by small interfering RNA synergizes with gemcitabine to inhibit the growth of pancreatic cancer

Rui Kong
- The Hepatosplenic Surgery Center, Department of General Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin 150001, China
Bei Sun
- The Hepatosplenic Surgery Center, Department of General Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin 150001, China
- Corresponding authors. Address: The Hepatosplenic Surgery Center, Department of General Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin 150001, China. Tel.: +64 9 9235935; fax: +64 9 3737942 (X. Sun), fax: +86 451 53643849 (B. Sun).
Hongchi Jiang
- The Hepatosplenic Surgery Center, Department of General Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin 150001, China
Shangha Pan
- The Hepatosplenic Surgery Center, Department of General Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin 150001, China
Hua Chen
- The Hepatosplenic Surgery Center, Department of General Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin 150001, China
Shuangjia Wang
- The Hepatosplenic Surgery Center, Department of General Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin 150001, China
Geoffrey W. Krissansen
- Department of Molecular Medicine and Pathology, Faculty of Medical and Health Sciences, The University of Auckland, Auckland 1005, New Zealand
Xueying Sun
- The Hepatosplenic Surgery Center, Department of General Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin 150001, China
- Department of Molecular Medicine and Pathology, Faculty of Medical and Health Sciences, The University of Auckland, Auckland 1005, New Zealand
- Corresponding authors. Address: The Hepatosplenic Surgery Center, Department of General Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin 150001, China. Tel.: +64 9 9235935; fax: +64 9 3737942 (X. Sun), fax: +86 451 53643849 (B. Sun).

Received 26 August 2009; received in revised form 4 October 2009; accepted 5 October 2009. published online 02 November 2009.

Abstract

The clinical benefit of gemcitabine for pancreatic cancer is low due to chemoresistance. Nuclear factor (NF)-κB, constitutively activated in pancreatic cancer, is a therapeutic target as it upregulates expression of genes controlling proliferation, apoptosis and angiogenesis. This study aimed to investigate whether downregulation of the p65 subunit of NF-κB by siRNA could enhance the efficacy of gemcitabine to treat pancreatic cancer. p65 siRNA synergized with gemcitabine to inhibit the proliferation and induce the apoptosis of pancreatic cancer cells in vitro and in vivo, and suppress the growth and angiogenesis of pancreatic tumors in nude mice. The mechanisms involved inhibition of NF-κB activity and consequent inhibition of Bcl-2, cyclin D1 and VEGF, and activation of caspase-3. The results suggest that downregulation of NF-κB p65 potentiates the efficacy of gemcitabine in combating pancreatic cancer.

Keywords: Pancreatic cancer, Nuclear factor-κB, Gemcitabine, Small interference RNA