Cell signaling and regulators of cell cycle as molecular targets for prostate cancer prevention by dietary agents

Prostate cancer (PCA) is the most common invasive malignancy and leading ca use (after lung) of cancer deaths in males. Since PCA is initially androgen -dependent, strategies are targeted toward androgen depletion fur its contr ol. However, tumor regrowth mostly occurs following this modality, and is a ndrogen independent. A loss of functional androgen receptor and an enhanced expression of growth factor receptors (e.g. erbB family members) and assoc iated ligands have been shown to he the causal genetic events in PCA progre ssion. These genetic alterations lead to an epigenetic mechanism where a fe ed-back autocrine loop between membrane receptor (e.g. epidermal growth fac tor receptor [erbB1] and associated ligand (e.g. transforming growth factor -alpha) results in an enhanced activation of extracellular signal-regulated protein kinase 1/2 (ERK1/2) as an essential component of the uncontrolled growth of PCA at an advanced and androgen-independent stage. Together, we r ationalized that inhibiting these epigenetic events would be useful in cont rolling advanced PCA growth. Dietary polyphenolic flavonoids and isoflavone s are being studied extensively as cancer preventive and interventive agent s. Therefore, we focused our attention on silymarin, genistein, and epigall ocatechin 3-gallate (EGCG), present in milk thistle, set. beans, and green tea, respectively. nle effect of these agents was assessed on the erbB1-Shc -ERK1/2 signal transduction pathway, cell cycle regulatory molecules, and c ell growth and death. In androgen-independent human prostate carcinoma DU14 5 cells, silymarin, genistein, and EGCG resulted in a significant to comple te inhibition of transforming growth factor-alpha-caused activation of memb rane receptor erbB1 followed by inhibition of downstream cytoplasmic signal ing target Shc activation and a decrease in its binding with erbB1, without an alteration in their protein expression. Silymarin and genistein also in hibited ERK1/2 activation, suggesting that these agents impair the activati on of erbB1-Shc-ERK1/2 signaling in DU145 cells. In the case of EGCG, a fur ther increase in ERK1/2 activation was observed that was related to its pro -oxidant and apoptotic activities. Silymarin, genistein, and EGCG also resu lted in a significant induction of Cip1/p21 and Kip1/p27 and a decrease in cyclin-dependent kinase (CDK) 4, but a moderate inhibition of CDK2, cyclin D1, and cyclin E was observed. An enhanced level of Cip1/p21 and Kip1/27 al so led to an increase in their binding to CDK4 and CDK2. Treatment of cells with silymarin, genistein, and EGCG also resulted in strong cell growth in hibition at lower doses, and complete inhibition at higher doses. In contra st to silymarin, higher doses of genistein also showed cell death. A more p rofound cytotoxic effect was observed in the case of EGCG, with strong cell death at lower doses and complete loss of viability at higher doses. Toget her, these results suggest that cell signaling and regulators of cell cycle are potential epigenetic molecular targets for prostate cancer prevention by dietary agents. More studies, therefore, are needed with these agents to explore their anticarcinogenic potential against human prostate cancer. BI OCHEM PHARMACOL 60;8:1051-1059, 2000. (C) 2000 Elsevier Science Inc.