Upregulation of Antioxidant Enzymes by Soybean‐Derived Glyceollins is Independent of p53 Expression in Human Colorectal Cancer Model

Abstract

Soybean‐Derived glyceollins were found to induce antioxidant/phase 2 detoxifying enzymes through Nrf2‐mediated signaling pathway, and thus protect cells from exogenous oxidative insult. As Nrf2 signaling pathway has been reported to be suppressed by p53, we hypothesized that Nrf2 activation by glyceollins could also be influenced by p53. Both p53‐wildtype and p53‐knockout HCT116 cells were treated with glyceollins, and then were examined for cell growth and Nrf2‐dependent cytoprotective reactions. Glyceollins treatment increased the expression levels of Nrf2 and its downstream enzymes in both p53‐wildtype and knockout cells in a similar fashion although the expression of p53 and p21 was significantly increased in p53‐wildtype HCT116 cells but not in p53‐knockout cells by glyceollins. In contrast, the treatment of p53‐knockout human colon carcinoma HCT116 cells with either sulforaphane or tBHQ caused dramatic increase in the reporter luciferase gene expression in the cells transfected with antioxidant response element (ARE) and luciferase gene construct, while the compounds led to marginal increase in the reporter gene expression in p53‐wildtype HCT116 cells. Moreover, sulforaphane induced cell growth in wild type HCT116 cells that was inhibited by treatment of SnPP, a HO‐1 inhibitor, while glyceollins did not affect the growth of both types of cells. Thus, the crosstalk between Nrf2 signaling pathway and p53 axis were found to be dependent on Nrf2 activators. In conclusion, these observations implicate the necessity of customized anticancer strategies depending on p53 status as well as the types of Nrf2 inducers.Support or Funding InformationThis study was funded by National Research Foundation (Grant No. R2014R1A2A2A01005773), Ministry of Science, ICT and Future Planning, Republic of Korea