PMID- 31181779 OWN - NLM STAT- MEDLINE DCOM- 20200106 LR - 20211204 IS - 1420-3049 (Electronic) IS - 1420-3049 (Linking) VI - 24 IP - 11 DP - 2019 Jun 8 TI - A Ferulic Acid Derivative FXS-3 Inhibits Proliferation and Metastasis of Human Lung Cancer A549 Cells via Positive JNK Signaling Pathway and Negative ERK/p38, AKT/mTOR and MEK/ERK Signaling Pathways. LID - 10.3390/molecules24112165 [doi] LID - 2165 AB - Lung cancer is one of the most common malignancies and is an increasing cause of cancer-related deaths. In our previous study, a series of ferulic acid (FA) derivatives were designed and synthesized; they exhibited positive anti-cancer activities, especially for a compound labelled FXS-3. In this study, a 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay was performed, wherein it revealed the inhibitory effect of FXS-3 on the proliferation and metastasis of human lung cancer A549 cells. The further flow cytometry assay showed that FXS-3 induced apoptosis of A549 cells induced cell cycle arrest at the G0/G1 phase. The trans-well migration and Matrigel invasion assays revealed that FXS-3 inhibited the migration and invasion of A549 cells. By the western blotting analysis, FXS-3 increased the expression of B-cell lymphoma-2 (Bcl-2) associated X protein (Bax)/Bcl-2 ratio, inhibited matrix metalloproteinase (MMP)-2 and MMP-9, and regulated the extracellular signal-regulated kinase (ERK)/p38, c-Jun N-terminal kinase (JNK), protein kinase B (AKT)/mechanistic target of rapamycin (mTOR), as well as mitogen-activated protein kinase (MEK)/ERK signaling pathways. The subsequent A549 xenograft-bearing mouse model and tail vein injection of A549 cells induced pulmonary tumor metastasis model showed that FXS-3 significantly restrained the tumor growth and metastasis. In conclusion, FXS-3 might inhibit proliferation and metastasis of human lung cancer A549 cells by positively regulating JNK signaling pathway and negativly regulating ERK/p38, AKT/mTOR, and MEK/ERK signaling pathways, which provides important scientific basis for the development of anti-cancer drugs about FA derivatives. FAU - Yue, Shi-Jun AU - Yue SJ AD - Key Laboratory of Shaanxi Administration of Traditional Chinese Medicine for TCM Compatibility, and State Key Laboratory of Research and Development of Characteristic Qin Medicine Resources (Cultivation), and Shaanxi Key Laboratory of Chinese Medicine Fundamentals and New Drugs Research, and Shaanxi Collaborative Innovation Center of Chinese Medicinal Resources Industrialization, Shaanxi University of Chinese Medicine, Xi'an 712046, Shaanxi Province, China. shijun_yue@163.com. FAU - Zhang, Peng-Xuan AU - Zhang PX AD - Key Laboratory of Shaanxi Administration of Traditional Chinese Medicine for TCM Compatibility, and State Key Laboratory of Research and Development of Characteristic Qin Medicine Resources (Cultivation), and Shaanxi Key Laboratory of Chinese Medicine Fundamentals and New Drugs Research, and Shaanxi Collaborative Innovation Center of Chinese Medicinal Resources Industrialization, Shaanxi University of Chinese Medicine, Xi'an 712046, Shaanxi Province, China. oucysj@126.com. FAU - Zhu, Yue AU - Zhu Y AD - Jiangsu Collaborative Innovation Center of Chinese Medicinal Resources Industrialization, and Jiangsu Key Laboratory for High Technology Research of TCM Formulae, and National and Local Collaborative Engineering Center of Chinese Medicinal Resources Industrialization and Formulae Innovative Medicine, Nanjing University of Chinese Medicine, Nanjing 210023, Jiangsu Province, China. zhuyue@njucm.edu.cn. FAU - Li, Nian-Guang AU - Li NG AD - Jiangsu Collaborative Innovation Center of Chinese Medicinal Resources Industrialization, and Jiangsu Key Laboratory for High Technology Research of TCM Formulae, and National and Local Collaborative Engineering Center of Chinese Medicinal Resources Industrialization and Formulae Innovative Medicine, Nanjing University of Chinese Medicine, Nanjing 210023, Jiangsu Province, China. linianguang@njucm.edu.cn. FAU - Chen, Yan-Yan AU - Chen YY AD - Key Laboratory of Shaanxi Administration of Traditional Chinese Medicine for TCM Compatibility, and State Key Laboratory of Research and Development of Characteristic Qin Medicine Resources (Cultivation), and Shaanxi Key Laboratory of Chinese Medicine Fundamentals and New Drugs Research, and Shaanxi Collaborative Innovation Center of Chinese Medicinal Resources Industrialization, Shaanxi University of Chinese Medicine, Xi'an 712046, Shaanxi Province, China. chenyanyan59@163.com. FAU - Li, Jia-Jia AU - Li JJ AD - Key Laboratory of Shaanxi Administration of Traditional Chinese Medicine for TCM Compatibility, and State Key Laboratory of Research and Development of Characteristic Qin Medicine Resources (Cultivation), and Shaanxi Key Laboratory of Chinese Medicine Fundamentals and New Drugs Research, and Shaanxi Collaborative Innovation Center of Chinese Medicinal Resources Industrialization, Shaanxi University of Chinese Medicine, Xi'an 712046, Shaanxi Province, China. ljjzhw2007@163.com. FAU - Zhang, Sai AU - Zhang S AD - Key Laboratory of Shaanxi Administration of Traditional Chinese Medicine for TCM Compatibility, and State Key Laboratory of Research and Development of Characteristic Qin Medicine Resources (Cultivation), and Shaanxi Key Laboratory of Chinese Medicine Fundamentals and New Drugs Research, and Shaanxi Collaborative Innovation Center of Chinese Medicinal Resources Industrialization, Shaanxi University of Chinese Medicine, Xi'an 712046, Shaanxi Province, China. zs18740484737@163.com. FAU - Jin, Ru-Yi AU - Jin RY AD - Key Laboratory of Shaanxi Administration of Traditional Chinese Medicine for TCM Compatibility, and State Key Laboratory of Research and Development of Characteristic Qin Medicine Resources (Cultivation), and Shaanxi Key Laboratory of Chinese Medicine Fundamentals and New Drugs Research, and Shaanxi Collaborative Innovation Center of Chinese Medicinal Resources Industrialization, Shaanxi University of Chinese Medicine, Xi'an 712046, Shaanxi Province, China. jinruyi335588@163.com. FAU - Yan, Hao AU - Yan H AD - Key Laboratory of Shaanxi Administration of Traditional Chinese Medicine for TCM Compatibility, and State Key Laboratory of Research and Development of Characteristic Qin Medicine Resources (Cultivation), and Shaanxi Key Laboratory of Chinese Medicine Fundamentals and New Drugs Research, and Shaanxi Collaborative Innovation Center of Chinese Medicinal Resources Industrialization, Shaanxi University of Chinese Medicine, Xi'an 712046, Shaanxi Province, China. yanhaohainan@126.com. FAU - Shi, Xu-Qin AU - Shi XQ AD - Jiangsu Collaborative Innovation Center of Chinese Medicinal Resources Industrialization, and Jiangsu Key Laboratory for High Technology Research of TCM Formulae, and National and Local Collaborative Engineering Center of Chinese Medicinal Resources Industrialization and Formulae Innovative Medicine, Nanjing University of Chinese Medicine, Nanjing 210023, Jiangsu Province, China. shixuqin@126.com. FAU - Tang, Yu-Ping AU - Tang YP AD - Key Laboratory of Shaanxi Administration of Traditional Chinese Medicine for TCM Compatibility, and State Key Laboratory of Research and Development of Characteristic Qin Medicine Resources (Cultivation), and Shaanxi Key Laboratory of Chinese Medicine Fundamentals and New Drugs Research, and Shaanxi Collaborative Innovation Center of Chinese Medicinal Resources Industrialization, Shaanxi University of Chinese Medicine, Xi'an 712046, Shaanxi Province, China. yupingtang@sntcm.edu.cn. AD - Jiangsu Collaborative Innovation Center of Chinese Medicinal Resources Industrialization, and Jiangsu Key Laboratory for High Technology Research of TCM Formulae, and National and Local Collaborative Engineering Center of Chinese Medicinal Resources Industrialization and Formulae Innovative Medicine, Nanjing University of Chinese Medicine, Nanjing 210023, Jiangsu Province, China. yupingtang@sntcm.edu.cn. FAU - Duan, Jin-Ao AU - Duan JA AD - Jiangsu Collaborative Innovation Center of Chinese Medicinal Resources Industrialization, and Jiangsu Key Laboratory for High Technology Research of TCM Formulae, and National and Local Collaborative Engineering Center of Chinese Medicinal Resources Industrialization and Formulae Innovative Medicine, Nanjing University of Chinese Medicine, Nanjing 210023, Jiangsu Province, China. dja@njucm.edu.cn. LA - eng GR - BRA2016387/333 High level Talents Training Project funded by Jiangsu Province/ GR - 81573714, 81773882/National Natural Science Foundation of China/ PT - Journal Article DEP - 20190608 PL - Switzerland TA - Molecules JT - Molecules (Basel, Switzerland) JID - 100964009 RN - 0 (Coumaric Acids) RN - AVM951ZWST (ferulic acid) RN - EC 2.7.11.1 (Proto-Oncogene Proteins c-akt) RN - EC 2.7.11.1 (TOR Serine-Threonine Kinases) RN - EC 2.7.12.2 (Mitogen-Activated Protein Kinase Kinases) SB - IM MH - A549 Cells MH - Animals MH - Apoptosis/drug effects MH - Cell Cycle Checkpoints/drug effects MH - Cell Movement/drug effects MH - Cell Proliferation/drug effects MH - Coumaric Acids/chemistry/*pharmacology MH - Humans MH - Lung Neoplasms/*enzymology/*pathology MH - MAP Kinase Signaling System/*drug effects MH - Male MH - Mice, Nude MH - Mitogen-Activated Protein Kinase Kinases/*metabolism MH - Neoplasm Invasiveness MH - Neoplasm Metastasis MH - Proto-Oncogene Proteins c-akt/*metabolism MH - TOR Serine-Threonine Kinases/*metabolism MH - Xenograft Model Antitumor Assays PMC - PMC6600170 OTO - NOTNLM OT - AKT/mTOR OT - ERK/p38 OT - FA derivatives OT - JNK OT - MEK/ERK. OT - lung cancer A549 cells COIS- The authors declare no conflict of interest. EDAT- 2019/06/12 06:00 MHDA- 2020/01/07 06:00 PMCR- 2019/06/08 CRDT- 2019/06/12 06:00 PHST- 2019/05/09 00:00 [received] PHST- 2019/05/28 00:00 [revised] PHST- 2019/06/01 00:00 [accepted] PHST- 2019/06/12 06:00 [entrez] PHST- 2019/06/12 06:00 [pubmed] PHST- 2020/01/07 06:00 [medline] PHST- 2019/06/08 00:00 [pmc-release] AID - molecules24112165 [pii] AID - molecules-24-02165 [pii] AID - 10.3390/molecules24112165 [doi] PST - epublish SO - Molecules. 2019 Jun 8;24(11):2165. doi: 10.3390/molecules24112165.