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 explore the mechanism of apoptosis and senescence, the proteins involved in SIRT1 signaling were analyzed. There was no significant change in SIRT1 expression with EX527 treatment, and EX527 did not decrease SIRT1 expression in GEM + EX527 treatment. Total p53 protein had no notable change with regard to EX527 or GEM treatment. AC-p53 protein of PANC-1 cells was significantly upregulated with EX527 treatment, but not in GEM-treated PANC-1 cells. Expression levels p21 were significantly enhanced when the cells were treated with EX527 or GEM. Moreover, FOXO3a expression was upregulated in EX527-treated cells, but no significant change of FOXO3a expression was shown after treatment with GEM. Compared to EX527 alone, although AC-p53 had no further increase, both FOXO3a and p21 expression were significantly increased (Fig. 8a). These results were also confirmed in ASPC-1 cells (Fig. 8b).
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.