1a.Objectives (from AD-416):
The objective of this agreement is to work together to conduct studies examining the effects of phytochemicals on cancer cells and cancer stem cells. Studies will focus on genes important in the process of carcinogenesis.
1b.Approach (from AD-416):
ARS will use cell culture models of prostate cancer cells or prostate cancer stem cells to test the effects of diet-derived phytochemicals on their ability to inhibit carcinogenesis. The focus will be on cellular pathways that may be important in the carcinogenesis process, including steroid hormone-related pathways, xenobiotic metabolism, etc. Gene expression of marker genes for specific pathways will be monitored to assess biological efficacies of various diet-derived components. The Cooperator will provide funding for material and supplies for the experiments as well as funding for personnel. ARS will conduct experiments and provide mentoring of visiting scientists involved in the project.
The molecular effects of a male sex steroid hormone on prostate cancer cells and interaction of diet-derived phytochemicals on this pathway were examined. The male sex steroid hormone dihydrotestosterone (DHT) was found to induce a time- and concentration-dependent increase in CCL2 mRNA levels in androgen-responsive human prostate cancer cells (LNCaP). CCL2 attracts monocytes and create a pro-inflammatory environment. Inflammation is a important promoter of tumor cell invasion and metastasis. 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. Both indole-3-carbinol and diindolylmethane, two cruciferous vegetable-derived phytochemicals, inhibited promotional effects of DHT on CCL2 expression and cell migration. These results demonstrate that androgens regulate CCL2 and promote a pro-inflammatory micro-environment, and that this process can be blocked by cruciferous vegetable-derived phytochemicals.