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Dehydroglyasperin C suppresses TPA‐induced cell transformation through direct inhibition of MKK4 and PI3K
Author(s) -
Lee Ji Hoon,
Kim JongEun,
Jang Young Jin,
Lee Charles C.,
Lim TaeGyu,
Jung Sung Keun,
Lee Eunjung,
Lim Soon Sung,
Heo Yong Seok,
Seo Sang Gwon,
Son Joe Eun,
Kim Jong Rhan,
Lee Chang Yong,
Lee Hyong Joo,
Lee Ki Won
Publication year - 2016
Publication title -
molecular carcinogenesis
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.254
H-Index - 97
eISSN - 1098-2744
pISSN - 0899-1987
DOI - 10.1002/mc.22302
Subject(s) - biology , pi3k/akt/mtor pathway , 12 o tetradecanoylphorbol 13 acetate , neoplastic transformation , activator (genetics) , tetradecanoylphorbol acetate , protein kinase b , kinase , cancer research , p38 mitogen activated protein kinases , cancer cell , protein kinase a , cell growth , microbiology and biotechnology , pharmacology , carcinogenesis , protein kinase c , cancer , biochemistry , phosphorylation , signal transduction , receptor , genetics , phorbol ester
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. © 2015 Wiley Periodicals, Inc.