The Curcumin Analogs 2-Pyridyl Cyclohexanone Induce Apoptosis via Inhibition of the JAK2-STAT3 Pathway in Human Esophageal Squamous Cell Carcinoma Cells

• Published in: Frontiers in pharmacology Vol. 9; p. 820
• Main Authors: Wang, Ying, Zhou, Pengjun, Qin, Shurong, Xu, Dandan, Liu, Yukun, Fu, Wuyu, Ruan, Bibo, Zhang, Li, Zhang, Yi, Wang, Xiao, Pan, Yuwei, Wang, Sheng, Yan, Haizhao, Qin, Jinhong, Wang, Xiaoyan, Liu, Qiuying, Du, Zhiyun, Liu, Zhong, Wang, Yifei
• Format: Journal Article
• Language: English
• Published: Switzerland Frontiers Media S.A 21-08-2018
• Subjects: 2-pyridyl cyclohexanone; apoptosis; Bcl-2; human esophageal squamous cell carcinoma; Pharmacology; STAT3; Bcl-2; 2-pyridyl cyclohexanone; human esophageal squamous cell carcinoma; apoptosis; STAT3
• ISSN: 1663-9812; 1663-9812
• DOI: 10.3389/fphar.2018.00820

Multiple modifications to the structure of curcumin have been investigated with an aim to improve its potency and biochemical properties. Previously, we have synthesized a series of curcumin analogs. In the present study, the anticancer effect of 2-pyridyl cyclohexanone, one of the curcumin analogs, on esophageal carcinoma Eca109 and EC9706 cell lines and its molecular mechanisms were investigated. 2-Pyridyl cyclohexanone inhibited the proliferation of Eca109 and EC9706 cells by inducing apoptosis as indicated by morphological changes, membrane phospholipid phosphatidylserine ectropion, caspase 3 activation, and cleavage of poly(ADP-ribose) polymerase. Mechanistic studies indicated that 2-pyridyl cyclohexanone disrupted mitochondrial membrane potential, disturbed the balance of the Bcl-2 family proteins, and triggered apoptosis via the mitochondria-mediated intrinsic pathway. In 2-pyridine cyclohexanone-treated cells, the phosphorylation levels of JAK2 and STAT3 were dose-dependently decreased and p38 and p-ERK signals were notably activated in a dose-dependent manner. Moreover, we found that the addition of S3I-201, a STAT3 inhibitor, led to a decreased expression level of Bcl-2 in Eca109 cells. The chromatin immunoprecipitation assay demonstrated that STAT3 bound to the promoter of Bcl-2 in the Eca109 cells. Furthermore, the mutation of four STAT3 binding sites (-1733/-1723, -1627/-1617, -807/-797, and -134/-124) on the promote of Bcl-2 gene alone attenuated the transcriptional activation of STAT3. In addition, down-regulation of STAT3 resulted in less of transcriptional activity of STAT3 on Bcl-2 expression. These data provide a potential molecular mechanism of the apoptotic induction function of 2-pyridyl cyclohexanone, and emphasize its important roles as a therapeutic agent for esophageal squamous carcinoma.