Suppression of NF-κB and NF-κB-Regulated Gene Expression by Apigenin through IκBα and IKK Pathway in TRAMP Mice

Aberrant Nuclear Factor-kappa appaB (NF-kappa B) activation due to rapid I kappa B alpha turnover and high basal I kappa B alpha kinase (IKK) activity has been frequently observed in prostate cancer. Apigenin, a naturally occurring plant flavone, exhibits anti-proliferative, anti-inflammatory and anti-carcinogenic activities by inhibiting NF-kappa B pathway, through a mechanism not fully understood. We found that apigenin feeding in microgram doses (bioavailable in humans) inhibited prostate tumorigenesis in TRAMP mice by interfering with NF-kappa B signaling. Apigenin feeding to TRAMP mice (20 and 50 mu g/mouse/day, 6 days/week for 20 weeks) exhibited significant decrease in tumor volumes of the prostate and completely abolished metastasis, which correlated with inhibition of NF-kappa B activation and binding to the DNA. Apigenin intake blocked phosphorylation and degradation of I kappa B alpha by inhibiting IKK activation, which in turn led to suppression of NF-kappa B activation. The expression of NF-kappa B-regulated gene products involved in proliferation (cyclin D1, and COX-2), anti-apoptosis (Bcl-2 and Bcl-xL), and angiogenesis (vascular endothelial growth factor) were also downregulated after apigenin feeding. These events correlated with the induction of apoptosis in tumor cells, as evident by increased cleaved caspase-3 labeling index in the dorsolateral prostate. Our results provide convincing evidence that apigenin inhibits IKK activation and restores the expression of I kappa B alpha, preventing it's phosphorylation in a fashion similar to that elicited by IKK and proteasomal inhibitors through suppression of NF-kappa B signaling pathway.