Licochalcone A, a natural inhibitor of c-Jun N-terminal kinase 1.

Abstract

The c-Jun N-terminal kinases (JNK) play an important role in many physiologic processes induced by numerous stress signals. Each JNK protein appears to have a distinct function in cancer, diabetes, or Parkinson's disease. Herein, we found that licochalcone A, a major phenolic constituent isolated from licorice root, suppressed JNK1 activity but had little effect on JNK2 in vitro activity. Although licochalcone A binds with JIP1 competitively with either JNK1 or JNK2, a computer simulation model showed that after licochalcone A binding, the ATP-binding cleft of JNK1 was distorted more substantially than that of JNK2. This could reduce the affinity of JNK1 more than JNK2 for ATP binding. Furthermore, licochalcone A inhibited JNK1-mediated, but not JNK2-mediated, c-Jun phosphorylation in both ex vivo and in vitro systems. We also observed that in colon and pancreatic cancer cell lines, JNK1 is highly expressed compared with normal cell lines. In cancer cell lines, treatment with licochalcone A or knocking down JNK1 expression suppressed colon and pancreatic cancer cell proliferation and colony formation. The inhibition resulted in G1 phase arrest and apoptosis. Moreover, an in vivo xenograft mouse study showed that licochalcone A treatment effectively suppressed the growth of HCT116 xenografts, without affecting the body weight of mice. These results show that licochalcone A is a selective JNK1 inhibitor. Therefore, we suggest that because of the critical role of JNK1 in colon cancer and pancreatic carcinogenesis, licochalcone A might have preventive or therapeutic potential against these devastating diseases.

• Authors: Ke Yao, Hanyong Chen, Mee-Hyun Lee, Haitao Li, Weiya Ma, Cong Peng, Nu Ry Song, Ki Won Lee, Ann M Bode, Ziming Dong, Zigang Dong
• Journal: Cancer prevention research (Philadelphia, Pa.) (Cancer Prev Res (Phila)) Vol. 7 Issue 1 Pg. 139-49 (Jan 2014) ISSN: 1940-6215 [Electronic] United States
• PMID: 24253317 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: ©2013 AACR.

Chemical References

• Adaptor Proteins, Signal Transducing
• Chalcones
• Enzyme Inhibitors
• MAPK8IP1 protein, human
• Plant Extracts
• Adenosine Triphosphate
• Mitogen-Activated Protein Kinase 9
• Mitogen-Activated Protein Kinase 8
• licochalcone A

Topics

• Adaptor Proteins, Signal Transducing (metabolism)
• Adenosine Triphosphate (metabolism)
• Animals
• Cell Adhesion
• Cell Line
• Cell Line, Tumor
• Chalcones (pharmacology)
• Colonic Neoplasms (drug therapy, metabolism)
• Computer Simulation
• Enzyme Inhibitors (pharmacology)
• Fibroblasts (metabolism)
• Glycyrrhiza (chemistry)
• HEK293 Cells
• Humans
• Mice
• Mice, Nude
• Mitogen-Activated Protein Kinase 8 (antagonists & inhibitors, metabolism)
• Mitogen-Activated Protein Kinase 9 (metabolism)
• Pancreatic Neoplasms (drug therapy, metabolism)
• Phosphorylation
• Plant Extracts (chemistry)
• Protein Binding
• Xenograft Model Antitumor Assays