Sirtuin 1 facilitates chemoresistance of pancreatic cancer cells by regulating adaptive response to chemotherapy-induced stress.
Bottom Line: 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.Thus, our results indicated a special role for SIRT1 in the regulation of adaptive response to chemotherapy-induced stress, which is involved in chemoresistance.
Affiliation: Hepatobiliary and Pancreatic Surgery, Zhejiang Provincial People's Hospital, Hangzhou, China; Pancreatic Disease Institute, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.Show MeSH
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Mentions: To further verify that the effect of EX527 on the chemosensitivity of pancreatic cancer cell lines is mainly due to inhibition of the SIRT1 pathway, EX527 and chemotherapy drugs were used to treated cell lines in which SIRT1 expression was deregulated by SIRT1 siRNA. Compared to control cells, the IC50 value of GEM was remarkably decreased in SIRT1-RNAi-PANC-1 cells (52.66 ± 2.65 vs 8.99 ± 3.02 μg/mL, P < 0.01) and SIRT1-RNAi-ASPC-1 cells (20.20 ± 1.98 vs 4.55 ± 2.29 μg/mL, P < 0.01). There was no further inhibition apparent in EX527-treated SIRT1-RNAi-PANC-1 and SIRT1-RNAi-ASPC-1 cells (IC50, 7.16 ± 2.92 and 3.57 ± 1.42 μg/mL, respectively, Fig. 4a). Furthermore, the Western blot results showed that EX527 had not further deregulated the SIRT1 expression in SIRT-RNAi transfected cells (Fig. 4b). These results revealed that the enhanced chemosensitivity of EX527 was critically through inhibiting SIRT1 activity.
Affiliation: Hepatobiliary and Pancreatic Surgery, Zhejiang Provincial People's Hospital, Hangzhou, China; Pancreatic Disease Institute, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.