These authors contributed equally to this work.
Sirtuin 1 facilitates chemoresistance of pancreatic cancer cells by regulating adaptive response to chemotherapy-induced stress
Version of Record online: 17 MAR 2014
© 2014 The Authors. Cancer Science published by Wiley Publishing Asia Pty Ltd on behalf of Japanese Cancer Association.
This is an open access article under the terms of the Creative Commons Attribution-NonCommercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.
Volume 105, Issue 4, pages 445–454, April 2014
How to Cite
Cancer Sci 105 (2014) 445–454
National Science Foundation Committee (NSFC) of China (30972900 and 81372666). Public Welfare Industry of Health of China (201202007).
- Issue online: 11 APR 2014
- Version of Record online: 17 MAR 2014
- Accepted manuscript online: 31 JAN 2014 09:49AM EST
- Manuscript Accepted: 22 JAN 2014
- Manuscript Revised: 7 JAN 2014
- Manuscript Received: 1 NOV 2013
- National Science Foundation Committee (NSFC) of China. Grant Numbers: 30972900, 81372666
- Public Welfare Industry of Health of China. Grant Number: 201202007
- Adaptive response;
- pancreatic cancer;
Chemotherapy drugs themselves may act as stressors to induce adaptive responses to promote the chemoresistance of cancer cells. Our previous research showed that sirtuin 1 (SIRT1) was overexpressed in pancreatic cancer patients and deregulation of SIRT1 with RNAi could enhance chemosensitivity. Thus, we hypothesized that SIRT1 might facilitate chemoresistance in pancreatic cancer cells through regulating the adaptive response to chemotherapy-induced stress. In the present study, SIRT1 in PANC-1, BXPC-3, and ASPC-1 cells was upregulated after treatment with gemcitabine. Moreover, the decrease in SIRT1 activity with special inhibitor EX527 had a synergic effect on chemotherapy with gemcitabine in PANC-1 and ASPC-1 cell lines, which significantly promoted apoptosis, senescence, and G0/G1 cycle arrest. Western blot results also showed that SIRT1, acetylated-p53, FOXO3a, and p21 were upregulated after combined treatment, whereas no obvious change was evident in total p53 protein. To further confirm the role of SIRT1 in clinical chemotherapy, SIRT1 was detected in eight pancreatic cancer tissues acquired by endoscopy ultrasonography guided fine needle aspiration biopsy before and after chemotherapy. Compared to before chemotherapy, SIRT1 was significantly increased after treatment with gemcitabine in six cases. Thus, our results indicated a special role for SIRT1 in the regulation of adaptive response to chemotherapy-induced stress, which is involved in chemoresistance. Moreover, it indicates that blocking SIRT1 activity with targeting drugs might be a novel strategy to reverse the chemoresistance of pancreatic cancer.