Plant flavonoid apigenin inhibits prostate carcinogenesis by suppressing β-catenin signaling pathways

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Deregulation of β-catenin signaling is an important event in the genesis of several human malignancies including prostate cancer. β-catenin is an intracellular anchoring protein and together with E-cadherin constitutes the adherent junction essential for epithelial cell homeostasis. Perturbation in the expression or function of these proteins results in loss of intercellular adhesion, with possible consequent cell transformation and cancer progression. Increased nuclear levels of β-catenin have been observed in prostate cancer, a finding that correlates with anti-apoptosis and enhanced cell invasiveness. Using the transgenic adenocarcinoma of the mouse prostate (TRAMP) model, we evaluated the efficacy of apigenin, a plant flavonoid commonly present in fruits and vegetables, in inhibiting prostate carcinogenesis and investigated its mechanism of action. Eight week old male TRAMP mice were randomly divided into three groups. Oral intake of apigenin at 20-μg/mouse/day to one group and at 50-μg/mouse/day to a second group (gavaged in 0.2 ml vehicle containing 0.5% methyl cellulose and 0.025% Tween 20) was provided for six days per week for 20 weeks; mice in the third group received vehicle only and served as controls. Studies from two independent experiments, conducted on 6 mice in each test group, showed that the cumulative incidence of prostate cancer development at 28 weeks of age in control animals was 100% (12/12) as observed by tumor palpation, whereas 75% (9/12), 42% (5/12) and 33% (4/12) of the animals exhibited distant metastases to lymph nodes, lungs, and liver. Apigenin feeding to TRAMP mice from 8-28 weeks of age was accompanied by a marked reduction in tumor growth with no evidence of metastasis. Apigenin feeding resulted in a significant decrease in dorso-lateral and ventral lobes of the prostate and genitourinary weight. Sequential MRI analysis documented that mice fed higher doses of apigenin had smaller prostate volumes than control mice and mice fed smaller doses of apigenin. Histopathological examination of apigenin-fed animals showed reduced proliferation, which correlated with serum apigenin levels. Feeding apigenin further resulted in increased levels of E-cadherin and decreased levels of nuclear β-catenin, and their key targets c-Myc and cyclin D1 in the dorso-lateral prostates. Treatment of DU145 human prostate cancer cells with 20 and 40 μM apigenin also increased protein levels of E-cadherin and reduced nuclear β-catenin expression, an effect similar to the exposure of cells to β-catenin siRNA. Diminished nuclear β-catenin levels exhibit reduced transcriptional activity, resulting in decreased c-Myc and cyclin D1. Taken together, these findings suggest that plant flavonoids, in particular apigenin may be beneficial in reducing the incidence and the aggressiveness of prostate cancer, at least in part by inhibiting β-catenin signaling pathways.