The Curcumin Analogs 2-Pyridyl Cyclohexanone Induce Apoptosis via Inhibition of the JAK2-STAT3 Pathway in Human Esophageal Squamous Cell Carcinoma Cells
Authors: Sheng Wang
Yifei Wang
Li Zhang
Pengjun Zhou
Yi Zhang
Qiuying Liu
Jinhong Qin
Zhong Liu
Wuyu Fu
Bibo Ruan
Haizhao Yan
Yukun Liu
Xiao Wang
Dandan Xu
Zhiyun Du
Shurong Qin
Xiaoyan Wang
Yuwei Pan
Ying Wang
Journal: Frontiers in pharmacology (2018)
Discipline: PHARMACOLOGY & TOXICOLOGY
Keywords: 2-pyridyl cyclohexanone; Bcl-2; STAT3; apoptosis; human esophageal squamous cell carcinoma.
Affiliations: Guangdong Provincial Key Laboratory of Bioengineering Medicine, Institute of Biomedicine, College of Life Science and Technology, Jinan University, Guangzhou, China., College of Food Science and Technology, Zhongkai University of Agriculture and Engineering, Guangzhou, China., Guangdong Food and Drug Vocational College, Guangzhou, China., School of Basic Courses, Guangdong Pharmaceutical University, Guangzhou, China., Cancer Center, Department of Surgery, Yale University, New Haven, CT, United States., Department of Pharmacy, Shenzhen People's Hospital, The Second Clinical Medical College of Jinan University, Shenzhen, China., College of Medicine, Jinan University, Guangzhou, China., Interdisciplinary Graduate School of Medicine and Engineering, University of Yamanashi, Yamanashi, Japan., Institute of Natural Medicine and Green Chemistry, School of Chemical Engineering and Light Industry, Guangdong University of Technology, Guangzhou, China.

Abstract:  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. 

Retracted: No

PubPeer comments:
 The GAPDH bands in Figure 4A and Figure 5 appear to share similarities, but the images differ as to dimensions and other details around the perimeters. Could the authors clarify if these are intended to be the same controls in both figures? *** Inverted (top is 4A, bottom is 5) ![file] *** Original, contrast enhanced ![file] , 
 I am Wang Ying, the first author of this paper. Thanks very much for your comments on our work. The GAPDH bands in Figure 4A and Figure 5 for EC9706 cell line are the same controls. The reason for the difference in dimension is that I stretched the length of the GAPDH band in Figure 5 to in order to align vertically with the other bands in this figure. I have not realize that the stretching would cause a certain distortion and change in the resolution of the picture. Again, we really appreciated your rigorous and serious work for our paper. , 
 #2 Thank you for your reply and clarification. ,