title: 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: WCU Biomodulation Major, Department of Agricultural Biotechnology and Center for Food and Bioconvergence, Seoul National University, Seoul, Republic of Korea.|Advanced Institutes of Convergence Technology, Seoul National University, Suwon, Republic of Korea.
authors: Ji Hoon
authors: JH
authors: Lee
authors: WCU Biomodulation Major, Department of Agricultural Biotechnology and Center for Food and Bioconvergence, Seoul National University, Seoul, Republic of Korea.|Advanced Institutes of Convergence Technology, Seoul National University, Suwon, Republic of Korea.|Research Institute of Bio Food Industry, Institute of Green Bio Science and Technology, Seoul National University, Pyeongchang, Republic of Korea.
authors: Jong-Eun
authors: JE
authors: Kim
authors: WCU Biomodulation Major, Department of Agricultural Biotechnology and Center for Food and Bioconvergence, Seoul National University, Seoul, Republic of Korea.|Division of Creative Food Science for Health, Korea Food Research Institute, Seongnam, Republic of Korea.
authors: Young Jin
authors: YJ
authors: Jang
authors: Department of Food Science and Technology, Cornell University, Ithaca, NY, 14456, USA.
authors: Charles C
authors: CC
authors: Lee
authors: WCU Biomodulation Major, Department of Agricultural Biotechnology and Center for Food and Bioconvergence, Seoul National University, Seoul, Republic of Korea.|Advanced Institutes of Convergence Technology, Seoul National University, Suwon, Republic of Korea.
authors: Tae-Gyu
authors: TG
authors: Lim
authors: WCU Biomodulation Major, Department of Agricultural Biotechnology and Center for Food and Bioconvergence, Seoul National University, Seoul, Republic of Korea.|Division of Creative Food Science for Health, Korea Food Research Institute, Seongnam, Republic of Korea.
authors: Sung Keun
authors: SK
authors: Jung
authors: WCU Biomodulation Major, Department of Agricultural Biotechnology and Center for Food and Bioconvergence, Seoul National University, Seoul, Republic of Korea.|Traditional Alcoholic Beverage Research Team, Korea Food Research Institute, Seongnam, Republic of Korea.
authors: Eunjung
authors: E
authors: Lee
authors: Department of Food Science and Nutrition, Hallym University, Chuncheon, Republic of Korea.
authors: Soon Sung
authors: SS
authors: Lim
authors: Department of Chemistry, Konkuk University, Seoul, Republic of Korea.
authors: Yong Seok
authors: YS
authors: Heo
authors: WCU Biomodulation Major, Department of Agricultural Biotechnology and Center for Food and Bioconvergence, Seoul National University, Seoul, Republic of Korea.|Advanced Institutes of Convergence Technology, Seoul National University, Suwon, Republic of Korea.
authors: Sang Gwon
authors: SG
authors: Seo
authors: WCU Biomodulation Major, Department of Agricultural Biotechnology and Center for Food and Bioconvergence, Seoul National University, Seoul, Republic of Korea.|Advanced Institutes of Convergence Technology, Seoul National University, Suwon, Republic of Korea.
authors: Joe Eun
authors: JE
authors: Son
authors: WCU Biomodulation Major, Department of Agricultural Biotechnology and Center for Food and Bioconvergence, Seoul National University, Seoul, Republic of Korea.|Advanced Institutes of Convergence Technology, Seoul National University, Suwon, Republic of Korea.
authors: Jong Rhan
authors: JR
authors: Kim
authors: Department of Food Science and Technology, Cornell University, Ithaca, NY, 14456, USA.|Department of Biochemistry, King Abdulaziz University, Jeddah, SA.
authors: Chang Yong
authors: CY
authors: Lee
authors: Research Institute of Bio Food Industry, Institute of Green Bio Science and Technology, Seoul National University, Pyeongchang, Republic of Korea.
authors: Hyong Joo
authors: HJ
authors: Lee
authors: WCU Biomodulation Major, Department of Agricultural Biotechnology and Center for Food and Bioconvergence, Seoul National University, Seoul, Republic of Korea.|Advanced Institutes of Convergence Technology, Seoul National University, Suwon, Republic of Korea.|Research Institute of Bio Food Industry, Institute of Green Bio Science and Technology, Seoul National University, Pyeongchang, Republic of Korea.|Institute on Aging, Seoul National University, Seoul, Republic of Korea.
authors: Ki Won
authors: KW
authors: Lee
mesh_terms: D000818:Animals; D001578:Benzopyrans / Q000494:pharmacology*; D002273:Carcinogens / Q000633:toxicity*; D002460:Cell Line; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D002471:Cell Transformation, Neoplastic / Q000139:chemically induced / Q000187:drug effects* / Q000378:metabolism; D051546:Cyclooxygenase 2 / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D048670:MAP Kinase Kinase 4 / Q000378:metabolism*; D051379:Mice; D016328:NF-kappa B / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D011485:Protein Binding / Q000187:drug effects; D015398:Signal Transduction / Q000187:drug effects; D013755:Tetradecanoylphorbol Acetate / Q000633:toxicity*; D018808:Transcription Factor AP-1 / Q000378:metabolism
chemical_list: D001578:Benzopyrans; D002273:Carcinogens; D016328:NF-kappa B; D018808:Transcription Factor AP-1; C548688:dehydroglyasperin C; C077623:Ptgs2 protein, mouse; D051546:Cyclooxygenase 2; D019869:Phosphatidylinositol 3-Kinases; D048670:MAP Kinase Kinase 4; D013755:Tetradecanoylphorbol Acetate
keywords: COX-2; MKK4; PI3K; cell transformation; dehydroglyasperin C