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.
Keywords: Adaptive response; EX527; SIRT1; gemcitabine; pancreatic cancer.
© 2014 The Authors. Cancer Science published by Wiley Publishing Asia Pty Ltd on behalf of Japanese Cancer Association.