Broccoli Consumption Interacts with GSTM1 to Perturb Oncogenic Signalling Pathways in the Prostate

Abstract

BackgroundEpidemiological studies suggest that people who consume more than one portion of cruciferous vegetables per week are at lower risk of both the incidence of prostate cancer and of developing aggressive prostate cancer but there is little understanding of the underlying mechanisms. In this study, we quantify and interpret changes in global gene expression patterns in the human prostate gland before, during and after a 12 month broccoli-rich diet.Methods and FindingsVolunteers were randomly assigned to either a broccoli-rich or a pea-rich diet. After six months there were no differences in gene expression between glutathione S-transferase mu 1 (GSTM1) positive and null individuals on the pea-rich diet but significant differences between GSTM1 genotypes on the broccoli-rich diet, associated with transforming growth factor beta 1 (TGFβ1) and epidermal growth factor (EGF) signalling pathways. Comparison of biopsies obtained pre and post intervention revealed more changes in gene expression occurred in individuals on a broccoli-rich diet than in those on a pea-rich diet. While there were changes in androgen signalling, regardless of diet, men on the broccoli diet had additional changes to mRNA processing, and TGFβ1, EGF and insulin signalling. We also provide evidence that sulforaphane (the isothiocyanate derived from 4-methylsuphinylbutyl glucosinolate that accumulates in broccoli) chemically interacts with TGFβ1, EGF and insulin peptides to form thioureas, and enhances TGFβ1/Smad-mediated transcription.ConclusionsThese findings suggest that consuming broccoli interacts with GSTM1 genotype to result in complex changes to signalling pathways associated with inflammation and carcinogenesis in the prostate. We propose that these changes may be mediated through the chemical interaction of isothiocyanates with signalling peptides in the plasma. This study provides, for the first time, experimental evidence obtained in humans to support observational studies that diets rich in cruciferous vegetables may reduce the risk of prostate cancer and other chronic disease.Trial RegistrationClinicalTrials.gov NCT00535977

Direct Modification of the Proinflammatory Cytokine Macrophage Migration Inhibitory Factor by Dietary Isothiocyanates

“…Furthermore, it shows that this reaction must be favorable in biological systems. Modification of amines by isothiocyanates has been previously observed on the N-terminal glycine and phenylalanine residues in insulin, the N-terminal aspartic acid residue in epidermal growth factor (26), and a lysine residue in the transient receptor potential-A1 channel (49). However, modification of amines has not previously been shown to occur either in cells or in vivo.…”

Effect of Sulforaphane in Men with Biochemical Recurrence after Radical Prostatectomy

“…Epigenetic regulation could be the key factor, as GSTP1 and GSTM1 hypermethylation and HDACs are prominently involved in prostate carcinogenesis and it has been shown that sulforaphane suppresses both of these mechanisms (24,25,37). These questions will be explored in future trials.…”

Staying a Step Ahead of Cancer

“…For instance, consumption of a known amount of the phytonutrient sulforaphane does not guarantee absorption of a predicted amount of anti-cancer molecule since differences in the glutathione S transferase M1 gene influences the metabolic rate of sulforaphane, a phytonutrient present in broccoli. The faster it is metabolized, the faster it is expelled from the body , Gasper et al 2005, Gross-Steinmeyer et al 2010, Joseph et al 2004, Lampe 2007, Lampe 2009, McWalter et al 2004, Riedl, Saxon and Diaz-Sanchez 2009, Ritz, Wan and Diaz-Sanchez 2007, Traka et al 2008. Similarly, a number of the nutrients, e.g.…”