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

Abstract

Aberrant Nuclear Factor-κappaB (NF-κB) activation due to rapid IκBα turnover and high basal IκBα 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-κB 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-κB signaling. Apigenin feeding to TRAMP mice (20 and 50 μg/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-κB activation and binding to the DNA. Apigenin intake blocked phosphorylation and degradation of IκBα by inhibiting IKK activation, which in turn led to suppression of NF-κB activation. The expression of NF-κB-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 IκBα, preventing it's phosphorylation in a fashion similar to that elicited by IKK and proteasomal inhibitors through suppression of NF-κB signaling pathway.

• Authors: Sanjeev Shukla, Eswar Shankar, Pingfu Fu, Gregory T MacLennan, Sanjay Gupta
• Journal: PloS one (PLoS One) Vol. 10 Issue 9 Pg. e0138710 ( 2015) ISSN: 1932-6203 [Electronic] United States
• PMID: 26379052 (Publication Type: Journal Article)

Chemical References

• Anti-Inflammatory Agents
• Anticarcinogenic Agents
• NF-kappa B
• Vascular Endothelial Growth Factor A
• Apigenin
• I-kappa B Kinase
• Caspase 3

Topics

• Animals
• Anti-Inflammatory Agents (pharmacology)
• Anticarcinogenic Agents (pharmacology)
• Apigenin (pharmacology)
• Apoptosis (drug effects)
• Caspase 3 (genetics)
• Cell Proliferation (drug effects, genetics)
• Down-Regulation (drug effects, genetics)
• Enzyme Activation (drug effects, genetics)
• Gene Expression Regulation, Neoplastic (drug effects, genetics)
• I-kappa B Kinase (genetics)
• Male
• Mice
• Mice, Inbred C57BL
• NF-kappa B (genetics)
• Neovascularization, Pathologic (drug therapy, genetics)
• Phosphorylation (drug effects, genetics)
• Prostatic Neoplasms (drug therapy, genetics)
• Signal Transduction (drug effects, genetics)
• Vascular Endothelial Growth Factor A (metabolism)