SIRT1 inhibits proliferation of pancreatic cancer cells expressing pancreatic adenocarcinoma up-regulated factor (PAUF), a novel oncogene, by suppression of β-catenin

Because we found in a recent study that pancreatic adenocarcinoma up-regulated factor (PAUF), a novel oncogene, induces a rapid proliferation of pancreatic cells by up-regulation of beta-catenin, we postulated that beta-catenin might be a target molecule for pancreatic cancer treatment. We thus speculated whether SIRT1, known to target beta-catenin in a colon cancer model, suppresses beta-catenin in those pancreatic cancer cells that express PAUF (Panc-PAUF). We further evaluated whether such suppression would lead to inhibition of the proliferation of these cells. The ectopic expression of either SIRT1 or resveratrol (an activator of SIRT1) suppressed levels of beta-catenin protein and its transcriptional activity in Panc-PAUF cells. Conversely, suppression of SIRT1 expression by siRNA enhanced beta-catenin expression and transcriptional activity. SIRT1 mutant analysis showed that nuclear localization of SIRT1 is not required for reduction of beta-catenin. Treatment with MG132, a proteasomal inhibitor, restored beta-catenin protein levels, suggesting that SIRT1-mediated degradation of beta-catenin requires proteasomal activity. It was reported that inhibition of GSK-3 beta or Siah-1 stabilizes beta-catenin in colon cancer cells, but suppression of GSK-3 beta or Siah-1 using siRNA in the presence of resveratrol instead diminished beta-catenin protein levels in Panc-PAUF cells. This suggests that GSK-3 beta and Siah-1 are not involved in SIRT1-mediated degradation of beta-catenin in the cells. Finally, activation of SIRT1 inhibited the proliferation of Panc-PAUF cells by down-regulation of cyclin-D1, a target molecule of beta-catenin. These results suggest that SIRT1 activation may be a therapeutic strategy for treatment of pancreatic cancer cells that express PAUF via the down-regulation of beta-catenin. (C) 2012 Elsevier Inc. All rights reserved.