Dehydroglyasperin C suppresses TPA-induced cell transformation through direct inhibition of MKK4 and PI3K.

Abstract

Bioactive natural compounds from plant-derived sources have received substantial interest due to their potential therapeutic and preventive effects toward various human diseases. Licorice (Glycyrrhiza), a frequently-used component in traditional oriental medicines, has been incorporated into recipes not only to enhance taste, but also to treat various conditions including inflammation, chronic fatigue syndrome, and even cancer. Dehydroglyasperin C (DGC) is a major isoflavone found in the root of licorice. In the present study, we investigated the cancer chemopreventive effect of DGC and the underlying molecular mechanisms involved, by analyzing its effects on 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced neoplastic cell transformation and cyclooxygenase (COX)-2 expression in JB6 P+ mouse epidermal cells. DGC treatment attenuated TPA-induced activator protein-1 (AP-1) and nuclear factor-κB (NF-κB) transcriptional activation, two major regulators of TPA-induced cell transformation, and COX-2 expression. TPA-induced phosphorylation of p38, JNK1/2 and Akt was also suppressed by DGC. Kinase assay data revealed that DGC inhibited the kinase activity of MKK4 and PI3K and this outcome was due to direct physical binding with DGC. Notably, DGC bound directly to MKK4 and PI3K in an ATP-competitive manner. Taken together, these results suggest that DGC exhibits cancer chemopreventive potential via its inhibitory effect on TPA-induced neoplastic cell transformation and COX-2 modulation through regulation of the MKK4 and PI3K pathways.

• Authors: Ji Hoon Lee, Jong-Eun Kim, Young Jin Jang, Charles C Lee, Tae-Gyu Lim, Sung Keun Jung, Eunjung Lee, Soon Sung Lim, Yong Seok Heo, Sang Gwon Seo, Joe Eun Son, Jong Rhan Kim, Chang Yong Lee, Hyong Joo Lee, Ki Won Lee
• Journal: Molecular carcinogenesis (Mol Carcinog) Vol. 55 Issue 5 Pg. 552-62 (May 2016) ISSN: 1098-2744 [Electronic] United States
• PMID: 25787879 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2015 Wiley Periodicals, Inc.

Chemical References

• Benzopyrans
• Carcinogens
• NF-kappa B
• Transcription Factor AP-1
• dehydroglyasperin C
• Ptgs2 protein, mouse
• Cyclooxygenase 2
• Phosphatidylinositol 3-Kinases
• MAP Kinase Kinase 4
• Tetradecanoylphorbol Acetate

Topics

• Animals
• Benzopyrans (pharmacology)
• Carcinogens (toxicity)
• Cell Line
• Cell Line, Tumor
• Cell Survival (drug effects)
• Cell Transformation, Neoplastic (chemically induced, drug effects, metabolism)
• Cyclooxygenase 2 (metabolism)
• Gene Expression Regulation, Neoplastic (drug effects)
• Humans
• MAP Kinase Kinase 4 (metabolism)
• Mice
• NF-kappa B (metabolism)
• Phosphatidylinositol 3-Kinases (metabolism)
• Protein Binding (drug effects)
• Signal Transduction (drug effects)
• Tetradecanoylphorbol Acetate (toxicity)
• Transcription Factor AP-1 (metabolism)