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Blockade of ß-Catenin Signaling by Plant Flavonoid Apigenin Suppresses Prostate Carcinogenesis in TRAMP Mice

Departments of ¹ Urology, ² Pathology, ³ Radiology, and ⁴ Epidemiology and Biostatistics, Case Western Reserve University and University Hospitals Case Medical Center; ⁵ Case Comprehensive Cancer Center, Cleveland, Ohio; and ⁶ Department of Cell Biology and Physiology, University of Pittsburgh, Pittsburgh, Pennsylvania

Requests for reprints: Sanjay Gupta, Department of Urology, The James and Eilleen Dicke Research Laboratory, Case Western Reserve University and University Hospitals Case Medical Center, 10900 Euclid Avenue, Cleveland, OH 44106. Phone: 216-368-6162; Fax: 216-368-0213; E-mail: sanjay.gupta{at}case.edu.

Deregulation of ß-catenin signaling is an important event in the genesis of several human malignancies including prostate cancer. We investigated the effects of apigenin, a naturally occurring plant flavone, on prostate carcinogenesis in TRAMP mice and further elucidated its mechanism of action. Oral intake of apigenin by gavage at doses of 20 and 50 µg/mouse/d, 6 days per week for 20 weeks, significantly decreased tumor volumes of the prostate as well as completely abolished distant-site metastases to lymph nodes, lungs, and liver in TRAMP mice. Apigenin-treated mice had significantly diminished weights of their genitourinary apparatuses and dorsolateral and ventral prostate lobes, compared with the control group, and showed reduced proliferation and increased apoptosis in the dorsolateral prostates, which correlated with elevated plasma apigenin levels. Continuous intake of apigenin up to 50 weeks by TRAMP mice significantly improved their overall survival. P.o. administration of apigenin further resulted in increased levels of E-cadherin and decreased levels of nuclear ß-catenin, c-Myc, and cyclin D1 in the dorsolateral prostates of TRAMP mice. Similar effects were noted in TRAMP mice with established tumors. Treatment of DU145 human prostate cancer cells with 10 and 20 µmol/L apigenin also increased protein levels of E-cadherin by 27% to 74%, inhibited nuclear translocation of ß-catenin and its retention in the cytoplasm, and decreased c-Myc and cyclin D1 levels, an effect similar to the exposure of cells to ß-catenin small interfering RNA. Our results indicate that apigenin effectively suppressed prostate carcinogenesis in TRAMP mice, at least in part, by blocking ß-catenin signaling. [Cancer Res 2007;67(14):6925–35]

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