The Curcumin Analogs 2-Pyridyl Cyclohexanone Induce Apoptosis via Inhibition of the JAK2–STAT3 Pathway in Human Esophageal Squamous Cell Carcinoma Cells
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,...
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Frontiers Media S.A.
2018-08-01
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| Series: | Frontiers in Pharmacology |
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| Online Access: | https://www.frontiersin.org/article/10.3389/fphar.2018.00820/full |
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| author | Ying Wang Ying Wang Pengjun Zhou Shurong Qin Dandan Xu Yukun Liu Wuyu Fu Bibo Ruan Li Zhang Yi Zhang Xiao Wang Yuwei Pan Sheng Wang Haizhao Yan Jinhong Qin Xiaoyan Wang Qiuying Liu Zhiyun Du Zhong Liu Yifei Wang |
| author_facet | Ying Wang Ying Wang Pengjun Zhou Shurong Qin Dandan Xu Yukun Liu Wuyu Fu Bibo Ruan Li Zhang Yi Zhang Xiao Wang Yuwei Pan Sheng Wang Haizhao Yan Jinhong Qin Xiaoyan Wang Qiuying Liu Zhiyun Du Zhong Liu Yifei Wang |
| author_sort | Ying Wang |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-04-12T10:23:58Z |
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| institution | Directory Open Access Journal |
| issn | 1663-9812 |
| language | English |
| last_indexed | 2024-04-12T10:23:58Z |
| publishDate | 2018-08-01 |
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| series | Frontiers in Pharmacology |
| spelling | doaj.art-7f994d0a5c4043d0a14488fe5ee84ab62022-12-22T03:37:01ZengFrontiers Media S.A.Frontiers in Pharmacology1663-98122018-08-01910.3389/fphar.2018.00820356829The Curcumin Analogs 2-Pyridyl Cyclohexanone Induce Apoptosis via Inhibition of the JAK2–STAT3 Pathway in Human Esophageal Squamous Cell Carcinoma CellsYing Wang0Ying Wang1Pengjun Zhou2Shurong Qin3Dandan Xu4Yukun Liu5Wuyu Fu6Bibo Ruan7Li Zhang8Yi Zhang9Xiao Wang10Yuwei Pan11Sheng Wang12Haizhao Yan13Jinhong Qin14Xiaoyan Wang15Qiuying Liu16Zhiyun Du17Zhong Liu18Yifei Wang19Guangdong Provincial Key Laboratory of Bioengineering Medicine, Institute of Biomedicine, College of Life Science and Technology, Jinan University, Guangzhou, ChinaCollege of Food Science and Technology, Zhongkai University of Agriculture and Engineering, Guangzhou, ChinaGuangdong Provincial Key Laboratory of Bioengineering Medicine, Institute of Biomedicine, College of Life Science and Technology, Jinan University, Guangzhou, ChinaGuangdong Provincial Key Laboratory of Bioengineering Medicine, Institute of Biomedicine, College of Life Science and Technology, Jinan University, Guangzhou, ChinaGuangdong Food and Drug Vocational College, Guangzhou, ChinaGuangdong Provincial Key Laboratory of Bioengineering Medicine, Institute of Biomedicine, College of Life Science and Technology, Jinan University, Guangzhou, ChinaSchool of Basic Courses, Guangdong Pharmaceutical University, Guangzhou, ChinaSchool of Basic Courses, Guangdong Pharmaceutical University, Guangzhou, ChinaGuangdong Provincial Key Laboratory of Bioengineering Medicine, Institute of Biomedicine, College of Life Science and Technology, Jinan University, Guangzhou, ChinaCancer Center, Department of Surgery, Yale University, New Haven, CT, United StatesDepartment of Pharmacy, Shenzhen People’s Hospital, The Second Clinical Medical College of Jinan University, Shenzhen, ChinaCollege of Medicine, Jinan University, Guangzhou, ChinaGuangdong Provincial Key Laboratory of Bioengineering Medicine, Institute of Biomedicine, College of Life Science and Technology, Jinan University, Guangzhou, ChinaInterdisciplinary Graduate School of Medicine and Engineering, University of Yamanashi, Yamanashi, JapanGuangdong Provincial Key Laboratory of Bioengineering Medicine, Institute of Biomedicine, College of Life Science and Technology, Jinan University, Guangzhou, ChinaGuangdong Provincial Key Laboratory of Bioengineering Medicine, Institute of Biomedicine, College of Life Science and Technology, Jinan University, Guangzhou, ChinaGuangdong Provincial Key Laboratory of Bioengineering Medicine, Institute of Biomedicine, College of Life Science and Technology, Jinan University, Guangzhou, ChinaInstitute of Natural Medicine and Green Chemistry, School of Chemical Engineering and Light Industry, Guangdong University of Technology, Guangzhou, ChinaGuangdong Provincial Key Laboratory of Bioengineering Medicine, Institute of Biomedicine, College of Life Science and Technology, Jinan University, Guangzhou, ChinaGuangdong Provincial Key Laboratory of Bioengineering Medicine, Institute of Biomedicine, College of Life Science and Technology, Jinan University, Guangzhou, ChinaMultiple 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.https://www.frontiersin.org/article/10.3389/fphar.2018.00820/full2-pyridyl cyclohexanoneSTAT3Bcl-2human esophageal squamous cell carcinomaapoptosis |
| spellingShingle | Ying Wang Ying Wang Pengjun Zhou Shurong Qin Dandan Xu Yukun Liu Wuyu Fu Bibo Ruan Li Zhang Yi Zhang Xiao Wang Yuwei Pan Sheng Wang Haizhao Yan Jinhong Qin Xiaoyan Wang Qiuying Liu Zhiyun Du Zhong Liu Yifei Wang The Curcumin Analogs 2-Pyridyl Cyclohexanone Induce Apoptosis via Inhibition of the JAK2–STAT3 Pathway in Human Esophageal Squamous Cell Carcinoma Cells Frontiers in Pharmacology 2-pyridyl cyclohexanone STAT3 Bcl-2 human esophageal squamous cell carcinoma apoptosis |
| title | The Curcumin Analogs 2-Pyridyl Cyclohexanone Induce Apoptosis via Inhibition of the JAK2–STAT3 Pathway in Human Esophageal Squamous Cell Carcinoma Cells |
| title_full | The Curcumin Analogs 2-Pyridyl Cyclohexanone Induce Apoptosis via Inhibition of the JAK2–STAT3 Pathway in Human Esophageal Squamous Cell Carcinoma Cells |
| title_fullStr | The Curcumin Analogs 2-Pyridyl Cyclohexanone Induce Apoptosis via Inhibition of the JAK2–STAT3 Pathway in Human Esophageal Squamous Cell Carcinoma Cells |
| title_full_unstemmed | The Curcumin Analogs 2-Pyridyl Cyclohexanone Induce Apoptosis via Inhibition of the JAK2–STAT3 Pathway in Human Esophageal Squamous Cell Carcinoma Cells |
| title_short | The Curcumin Analogs 2-Pyridyl Cyclohexanone Induce Apoptosis via Inhibition of the JAK2–STAT3 Pathway in Human Esophageal Squamous Cell Carcinoma Cells |
| title_sort | curcumin analogs 2 pyridyl cyclohexanone induce apoptosis via inhibition of the jak2 stat3 pathway in human esophageal squamous cell carcinoma cells |
| topic | 2-pyridyl cyclohexanone STAT3 Bcl-2 human esophageal squamous cell carcinoma apoptosis |
| url | https://www.frontiersin.org/article/10.3389/fphar.2018.00820/full |
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