Licochalcone A, a natural inhibitor of c-Jun N-terminal kinase 1
Menée sur des lignées cellulaires cancéreuses et à l'aide de xénogreffes, cette étude met en évidence un effet inhibiteur de la licochalcone A (une substance phénolique présente dans la racine de la réglisse) sur l'expression de JNK1, une kinase impliquée dans la carcinogenèse du côlon et du pancréas
The c-Jun N-terminal kinases (JNKs) play an important role in many physiological 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 demonstrate that licochalcone A is a selective JNK1 inhibitor. Therefore, we suggest that because of JNK1's critical role in colon cancer and pancreatic carcinogenesis, licochalcone A might have preventive or therapeutic potential against these devastating diseases.