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United States Department of Agriculture

Agricultural Research Service

Research Project: MOLECULAR AND CELLULAR BASES OF HEALTH-PROMOTING FOOD COMPONENTS IN PREVENTION OF CHRONIC DISEASES

Location: Diet, Genomics and Immunology Lab

Title: Indole-3-carbinol and 3’, 3’-diindolylmethane modulate androgen effect up-regulation on C-C chemokine ligand 2 and monocyte attraction to prostate cancer cells

Authors
item Kim, Eun -
item Kim, Young -
item Milner, John
item Wang, Thomas

Submitted to: Cancer Prevention Research
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: March 29, 2013
Publication Date: June 12, 2013
Citation: Kim, E.K., Kim, Y.S., Milner, J.A., Wang, T.T. 2013. Indole-3-carbinol and 3’, 3’-diindolylmethane modulate androgen effect up-regulation on C-C chemokine ligand 2 and monocyte attraction to prostate cancer cells. Cancer Prevention Research. 6(6):519-529.

Interpretive Summary: The broccoli-derived compounds, indole-3-Carbinol (I3C) and diindolylmethane (DIM), are promising diet-derived prostate cancer protective compounds. But the mechanisms of action for these compounds remain largely unclear. Inflammation has a role in prostate cancer development. Recruitment of pro-inflammatory immune cells to the tumor site is mediated by C-C chemokine ligand 2 (CCL2) through binding to its receptor CCR2. We hypothesized that the male sex hormone/androgen dihydrotestosterone (DHT) could modulate CCL2 expression in hormone-responsive prostate cancer cells and thereby promote recruitment of pro-inflammatory immune cells and inflammation. We showed previously that broccoli-derived compounds indole-3-carbinol (I3C) and 3,3’-diindolylmethane (DIM) inhibit androgen-dependent pathway. We also reasoned that I3C and DIM could modulate the effect of androgen on CCL2-mediated pathways. Dihydrotestosterone was found to induce a time (0-72 hrs) and concentration-dependent (0-1 nM) 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 DHT was mediated through an androgen receptor (AR)-dependent pathway as small inhibitor RNA (siRNA) against AR negated the induction of CCL2. Although DHT also induced TWIST-1, an epithelial-mesenchymal transition related factor and purported inducer of CCL2, blocking its expression with siRNA did not inhibit DHT 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 CCL2. Both I3C and DIM inhibited promotional effects of DHT on CCL2 and THP-1 cell migration. These results demonstrate that androgen regulates CCL2 and promotes inflammatory micro-environments in prostate tumors, and that this process can be blocked by broccoli-derived compounds. The information serves as an important basis for future investigation diet-derived agent that may regulate inflammation and prostate cancer development. This work will benefit basic as well as translational research science.

Technical 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’-diindolylmethane (DIM) on androgen-dependent pathways, we also reasoned that I3C and DIM could modulate the effect of androgen on CCL2-mediated pathways. Dihydrotestosterone (DHT) was found to induce a time (0-72 hrs) and concentration-dependent (0-1 nM) 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 DHT was mediated through an androgen receptor (AR)-dependent pathway as small inhibitor RNA against AR negated the induction of CCL2. Although DHT also induced TWIST1 mRNA, an epithelial-mesenchymal transition related factor and purported inducer of CCL2, blocking its expression with small inhibitor RNA did not inhibit DHT 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 DHT on CCL2 and migration. These results demonstrate that androgen regulates CCL2 and promotes inflammatory micro-environments in prostate tumors, and that this process can be blocked by broccoli-derived compounds.

Last Modified: 8/30/2014
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