Activation of Nrf2 signaling pathway by glyceollins is independent of p53 in human colon cancer model

2^nd International Congress on Restorative & Alternative Medicine

November 06-07, 2017 | Vienna, Austria

Jong-Sang Kim

Kyungpook National University, South Korea

Posters & Accepted Abstracts: Altern Integr Med

Abstract :

Glyceollins, soybean-derived phytoalexins are reported to induce antioxidant and phase two detoxifying enzymes through nuclear factor (erythroid-derived 2)-like 2 (Nrf2)-mediated signaling pathway and thus protect normal cells from xenobiotic or cellular stress stimuli. Serendipitously, we observed that low doses of glyceollins promoted the proliferation of colorectal cancer cells carrying normal p53 gene while the compounds inhibited the growth of p53-negative colon cancer cells in a dose-dependent manner. As p53 is known to activate its downstream gene p21 that interferes Kelch-like ECH-associated protein 1 (Keap1)/Nrf2 heterodimer formation, we hypothesized that glyceollins at low doses stimulate Nrf2 signaling pathway by up-regulating p53-mediated p21 expression, leading to proliferation of p53-positive colon carcinoma cells. When treated with glyceollins, the growth of wild type (wt) p53 HCT116 cells was increased by glyceollins in the range of 1-20 �¼g/mL while the growth of HT29 and Caco-2 cells carrying mutated p53 was unaffected or gradually decreased by glyceollins treatment. Glyceollins led to significantly increased expressions of p53 and p21 in wt p53 HCT116 cells, but did not affect the gene expression in p53-knockout HCT116 cells. However, the expression of Nrf2 and its downstream genes was significantly enhanced both in p53-mutant cells as well as p53-wild type cells, suggesting that glyceollins promote Nrf2 signaling pathway in a p53-independent manner. In contrast, sulforaphane and tert-butylhydroquinone, well-known activators of Nrf2 signaling pathway did not activate Nrf2 signaling pathway in p53 wild type HCT116 cells although they stimulated Nrf2 signaling pathway in p53-mutant cells. In conclusion, the activation mechanism of Nrf2 signaling pathway by glyceollins is likely to be different from common phase two enzyme inducers and not suppressed by p53.