Apigenin blocks tumor growth, invasion and metastasis by upregulation of maspin in TRAMP model

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Acquisition of metastatic capability during prostate cancer progression leads to clinically incurable malignancy and accounts for the majority of deaths from this disease. Metastasis involves multiple processes, including invasion, intravasation, extravasation and growth at the secondary site. Recent studies have demonstrated that the metastasis process is regulated by IKKα, the upstream kinase that regulates nuclear transcription factor, NF-κB through down-modulation of maspin (SERPINB5, PI5), in transgenic adenocarcinoma of the mouse prostate (TRAMP) model. Maspin is a unique member of the serpin (serine protease inhibitor) family whose expression is lost during cancer progression. Maspin re-expression results in restoration of differentiation in epithelial cells, and inhibition of tumor cell motility and invasion. We have previously demonstrated that oral administration of apigenin, a plant flavone, causes reduced growth of primary tumors with complete inhibition of distant metastasis in TRAMP mice. However, the molecular mechanism(s) through which apigenin inhibits cancer metastases has not been fully elucidated. Age-dependent analysis of dorsolateral prostate tissue from TRAMP mice and their non-transgenic littermates demonstrated a progressive decrease in maspin expression which correlated with increased activity of IKKα, IκBα and its phosphorylation in TRAMP mice, compared to their non-transgenic littermates. Apigenin administration at doses of 20 and 50 μg/mouse/day, 6 days per week for 20 weeks significantly increased maspin expression in the dorsolateral prostates of TRAMP mice which occurred in dose-dependent fashion. These events were followed by reduction in the activity of IKKα and IκBα and correlated with nuclear levels of NF-κB/p65 in the prostates of these mice. Furthermore, oral administration of apigenin resulted in decreased levels of MMP-9 and uPA in the prostates of TRAMP mice; additionally, exposure of DU145 human prostate cancer cells to apigenin increased the protein levels of maspin, inhibited nuclear translocation of NF-κB/p65, and resulted in reduced activity of IKKα and IκBα, an effect similar to the exposure of cells to recombinant maspin. Similar effects were observed at the transcriptional level, where exposure of DU145 cells to apigenin resulted in increased mRNA levels of maspin and IκBα which correlated with reduced invasiveness and migration in these cells. Overall, these results suggest that maspin can interfere with the ability of prostatic adenocarcinoma to progress through the stages of invasion and metastasis, and provide a rationale for the strong protective effects that apigenin has been demonstrated to exert against prostate cancer progression.