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19406207capr130117-sup-fig_s4.pdf (126.22 kB)

Supplementary Figure 4 from Licochalcone A, a Natural Inhibitor of c-Jun N-Terminal Kinase 1

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posted on 2023-04-03, 19:29 authored by 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

PDF file 126K, Figure S4. Licochalcone A suppresses breast and liver cancer cell proliferation and colony formation mediated through JNK1. (A) Licochalcone A suppresses SK-BR-3 breast cancer and HepG2 liver cancer cell proliferation. SK-BR-3 or HepG2 cells (1 x 103) cells were seeded, cultured overnight, and then treated with different doses of lichochalcone A and proliferation was measured by MTS assay at the indicated time point to assess time- and dose-dependent effects. (B) Licochalcone A suppresses SK-BR-3 breast cancer and HepG2 liver cancer cell anchorage-independent growth. SK-BR-3 or HepG2 cells (8 x 103/mL) were exposed to different doses of lichochalcone A in 1 mL of 0.3% BME agar containing 10% FBS. Each dose was repeated in triplicate wells. The cultures were maintained in a 37{degree sign}C, 5% CO2 incubator for 10 d and then colonies were counted using a microscope and the Image-Pro PLUS (vs. 4) computer software program. (D) JNK1 knockdown in SK-BR-3 breast cancer and HepG2 liver cancer cells suppresses anchorage-independent growth. SK-BR-3 or HepG2 cells stably expressing sh-mock or sh-JNK1 were examined for colony growth under anchorage-independent conditions. Cells (8 � 103/mL) were mixed in 1 mL of 0.3% BME agar containing 10% FBS. The cultures were maintained in a 37{degree sign}C, 5% CO2 incubator for 10 d and then colonies were counted using a microscope and the Image-Pro PLUS (vs. 4) computer software program. For A-C, data are shown as mean values plus-minus S.D. obtained from triplicate experiments. Significant differences were evaluated using factorial ANOVA (Scheffe post hoc) analysis and the asterisks indicate a significant effect (*, p < 0.01)

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ARTICLE 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. Cancer Prev Res; 7(1); 139–49. ©2013 AACR.

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