Broccoli‐derived compounds modulate androgen up‐regulation of C‐C chemokine ligand 2 and enhancement of monocyte attraction to prostate cancer cells

Abstract

Inflammation plays a key 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′‐diindolylmethane (DIM) on androgen‐dependent pathway, we also reasoned that I3C and DIM could modulate the effect of androgen on CCL2‐mediated pathways. We found that androgen dihydrotestosterone (DHT) induced time (0–72 hrs) and concentration‐dependent (0–1 nM) increases in CCL2 mRNA levels in the androgen‐responsive human prostate cancer cell LNCaP. The increase in CCL2 mRNA corresponded to increased secretion of CCL2 protein by LNCaP cells. This effect of DHT was mediated through an androgen receptor (AR)‐dependent pathway as small inhibitor RNA against AR negated the induction of CCL2 mRNA by DHT. Moreover, conditioned media from androgen‐treated cells promoted human monocyte THP‐1 cell migration. Both I3C and DIM inhibited promotional effects of DHT on CCL2 and migration. These results suggested that androgen regulates CCL2 and promotes inflammatory micro‐environments in prostate tumors, and this process can be regulated by broccoli‐derived compounds.