The Curcumin Analogs 2-Pyridyl Cyclohexanone Induce Apoptosis via Inhibition of the JAK2–STAT3 Pathway in Human Esophageal Squamous Cell Carcinoma Cells
| Autor: | Jin-Hong Qin, Yi Zhang, Shurong Qin, Sheng Wang, Liu Yukun, Xiao Wang, Zhiyun Du, Hai-Zhao Yan, Qiu-Ying Liu, Ying Wang, Li Zhang, Dan-Dan Xu, Peng-Jun Zhou, Bi-Bo Ruan, Yu-Wei Pan, Xiaoyan Wang, Wu-Yu Fu, Wang Yifei, Zhong Liu |
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| Jazyk: | angličtina |
| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
p38 mitogen-activated protein kinases Caspase 3 2-pyridyl cyclohexanone STAT3 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine Bcl-2 Pharmacology (medical) Original Research Pharmacology human esophageal squamous cell carcinoma lcsh:RM1-950 apoptosis Phosphatidylserine Molecular biology Squamous carcinoma 030104 developmental biology lcsh:Therapeutics. Pharmacology chemistry Apoptosis Cell culture 030220 oncology & carcinogenesis Curcumin Chromatin immunoprecipitation |
| Zdroj: | Frontiers in Pharmacology Frontiers in Pharmacology, Vol 9 (2018) |
| ISSN: | 1663-9812 |
| DOI: | 10.3389/fphar.2018.00820 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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