Indole-3-Carbinol and 3′,3′-Diindolylmethane Modulate Androgen's Effect on C-C Chemokine Ligand 2 and Monocyte Attraction to Prostate Cancer Cells

Abstract

Inflammation has a role in prostate tumorigenesis. Recruitment of inflammatory monocytes to the tumor site is mediated by C-C chemokine ligand 2 (CCL2) through binding to its receptor CCR2. We hypothesized that androgen could modulate CCL2 expression in hormone-responsive prostate cancer cells and thereby promote recruitment of monocytes. Given the inhibitory effect of broccoli-derived compounds indole-3-carbinol (I3C) and 3,3 0 -diindolylmethane (DIM) on androgen-dependent pathways, we also reasoned that I3C and DIM could modulate the effect of androgen on CCL2-mediated pathways. Dihydrotestosterone was found to induce a time-dependent (0-72 hours) and concentration-dependent (0-1 nmol/L) increase in CCL2 mRNA levels in androgen-responsive human prostate cancer cells (LNCaP). This increase in CCL2 mRNA corresponded with increased secretion of CCL2 protein. The effect of dihydrotestosterone was mediated through an androgen receptor (AR)-dependent pathway as small inhibitor RNA against AR negated the induction of CCL2. Although dihydrotestosterone also induced TWIST1 mRNA, an epithelialmesenchymal transition-related factor, and purported inducer of CCL2, blocking its expression with small inhibitor RNA did not inhibit dihydrotestosterone induction of CCL2 mRNA. Moreover, conditioned media from androgen-treated cells promoted human monocyte THP-1 cell migration and this effect was blocked by antibody against CCL-2. Both I3C and DIM inhibited promotional effects of dihydrotestosterone on CCL2 and migration. These results show that androgen may regulate CCL2 and promote inflammatory microenvironment in prostate tumors and that this process can be blocked by broccoli-derived compounds.Cancer Prev Res; 6(6); 519-29. Ó2013 AACR.

Therapeutic effects of 3,3′-diindolylmethane on the alveolar bone in mice with experimentally induced periodontitis

“…Among various inflammatory cytokines, IL-1b and IL-6 play important roles in the expression of differentiation factors and activation of osteoclasts, which results in CT degradation and bone resorption [26]. A previous study reported that DIM can reduce the expression of IL-1b and IL-6 to delay prostate tumour growth and angiogenesis [27]. In vitro, the effects of DIM on IL-1b and IL-6 Note: All results are expressed as means § SD.…”

Inhibition of Tumor Growth by Dietary Indole-3-Carbinol in a Prostate Cancer Xenograft Model May Be Associated with Disrupted Gut Microbial Interactions

“…These indoles are known for their chemopreventive effects on hormone-dependent cancers such as prostate cancer [ 8 ]. It has been shown that I3C/DIM inhibit proliferation, migration, and invasion of prostate cancer cells in vitro by targeting a wide spectrum of signal pathways governing hormonal homeostasis, cell cycle progression, apoptosis, and DNA repair [ 9 , 10 , 11 ]. Several nuclear transcription factor-mediated pathways related to these biological processes have been reported to be modulated by I3C/DIM [ 12 ].…”

Elucidating the Role of CD84 and AHR in Modulation of LPS-Induced Cytokines Production by Cruciferous Vegetable-Derived Compounds Indole-3-Carbinol and 3,3′-Diindolylmethane

“…In vitro, both I3C and DIM appear to be pleotropic and can exert their effects through multiple pathways which include modulation of androgen-dependent pathways and the AHR mediated pathway [ 23 , 24 ]. Previously, we have shown that I3C and DIM, through androgen-dependent pathways, modulate the interaction between prostate cancer cells and macrophages by regulating the production of chemokine CCL2 by prostate cancer cells [ 29 ]. CCL2 is a pro-inflammatory chemokine that attracts monocytes to tumor sites [ 30 ].…”

“…THP-1 is a monocytic cell line that can be differentiated into macrophage. Additionally, we have also shown that THP-1 can be attracted by cancer cells [ 29 ].…”