Genistein, a Dietary Isoflavone, Down-Regulates the MDM2 Oncogene at Both Transcriptional and Posttranslational Levels

Abstract

Although genistein has chemopreventive effects in several human malignancies, including cancers of the breast, colon, and prostate, the mechanisms of action are not fully understood. Herein we report novel mechanisms whereby genistein down-regulates the MDM2 oncogene, perhaps explaining some of its anticancer activities. In a dose-and time-dependent manner, genistein reduced MDM2 protein and mRNA levels in human cell lines of breast, colon, and prostate cancer; primary fibroblasts; and breast epithelial cells. The inhibitory effects were found at both transcriptional and posttranslational levels and were independent of tyrosine kinase pathways. We found that the NFAT transcription site in the region between À132 and +33 in the MDM2 P2 promoter was responsive to genistein. At the posttranslational level, genistein induced ubiquitination of MDM2, which led to its degradation. Additionally, genistein induced apoptosis and G 2 arrest and inhibited proliferation in a variety of human cancer cell lines, regardless of p53 status. We further showed that MDM2 overexpression abrogated genistein-induced apoptosis in vitro and that genistein inhibited MDM2 expression and tumor growth in PC3 xenografts. In conclusion, genistein directly down-regulates the MDM2 oncogene, representing a novel mechanism of its action that may have implications for its chemopreventive and chemotherapeutic effects. (Cancer Res 2005; 65(18): 8200-8)

Transcription Factor NFAT1 Activates the mdm2 Oncogene Independent of p53

“…In addition, the ectopic activation of NFAT1 activates c-Myc, which is a critical mechanism for pancreatic cancer cell growth in vitro and in vivo (29,30). In our previous work, we have demonstrated that the mdm2 transcription is down-regulated by a dietary isoflavone, genistein, in multiple cancer cell lines (31). Although the underlying mechanism is not fully understood, our preliminary results suggest that the NFAT transcription factors may be involved in the regulation of mdm2 mRNA expression.…”

“…Colony Formation, Apoptosis, Quantitative PCR, and Luciferase Reporter Assays-The colony formation assay, cell apoptosis assay, quantitative PCR assay, and luciferase reporter assay were performed as described previously (31).…”

Dietary Fibre and the Risk of Colorectal Cancer: a Case-Control Study

“…These nutrients have protective effects against colorectal cancer. Previous studies have shown that these nutrients can maintain DNA synthesis and methylation (Mason et al, 1996), modulate signal pathways in malignant transformation (Li et al, 2005), inhibit cell growth and induce apoptosis (Bennink, 2001). Foods that lack these nutrients are related to an increased risk of colorectal cancer (Potter, 1999).…”

Luteolin inhibits invasion of prostate cancer PC3 cells through E-cadherin

“…2). A few of flavonoids were found to inhibit expression of mdm2 (21,37). Mdm2 can be phosphorylated by AKT (28,38), which increases stability of mdm2.…”