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

  • Mol Carcinog. 2016 May;55(5):552-62. doi: 10.1002/mc.22302.
Ji Hoon Lee  1  2 ,  Jong-Eun Kim  1  2  3 ,  Young Jin Jang  1  4 ,  Charles C Lee  5 ,  Tae-Gyu Lim  1  2 ,  Sung Keun Jung  1  4 ,  Eunjung Lee  1  6 ,  Soon Sung Lim  7 ,  Yong Seok Heo  8 ,  Sang Gwon Seo  1  2 ,  Joe Eun Son  1  2 ,  Jong Rhan Kim  1  2 ,  Chang Yong Lee  5  9 ,  Hyong Joo Lee  3 ,  Ki Won Lee  1  2  3  10
Affiliations
  • 1. WCU Biomodulation Major, Department of Agricultural Biotechnology and Center for Food and Bioconvergence, Seoul National University, Seoul, Republic of Korea.
  • 2. Advanced Institutes of Convergence Technology, Seoul National University, Suwon, Republic of Korea.
  • 3. Research Institute of Bio Food Industry, Institute of Green Bio Science and Technology, Seoul National University, Pyeongchang, Republic of Korea.
  • 4. Division of Creative Food Science for Health, Korea Food Research Institute, Seongnam, Republic of Korea.
  • 5. Department of Food Science and Technology, Cornell University, Ithaca, NY, 14456, USA.
  • 6. Traditional Alcoholic Beverage Research Team, Korea Food Research Institute, Seongnam, Republic of Korea.
  • 7. Department of Food Science and Nutrition, Hallym University, Chuncheon, Republic of Korea.
  • 8. Department of Chemistry, Konkuk University, Seoul, Republic of Korea.
  • 9. Department of Biochemistry, King Abdulaziz University, Jeddah, SA.
  • 10. Institute on Aging, Seoul National University, Seoul, Republic of Korea.
PMID: 25787879 DOI: 10.1002/mc.22302
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.

Keywords
COX-2; MKK4; PI3K; cell transformation; dehydroglyasperin C.
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