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.

Apigenin as an effective anticancer natural product: Spotlight on TRAIL, WNT/β‐catenin, JAK‐STAT pathways, and microRNAs

“…Apigenin administration inhibited prostate tumorigenesis in TRAMP mice and interfered with the NF‐κB‐driven pathway. Apigenin significantly reduced tumor volumes of the prostate in TRAMP mice . Apigenin significantly inhibited tumor growth and blood‐borne metastasis in mice subcutaneously injected with PLC/PRF/5 cells.…”

EGCG sensitizes human nasopharyngeal carcinoma cells to TRAIL-mediated apoptosis by activation NF-κB

“…Effects of EGCG on the expression of anti-apoptotic proteins. Changes of expression of members of the Bcl-2 family and inhibitor of apoptosis (IAP) family result in chemotherapy resistance of NPC cells [16,17]. NF-κB inhibits apoptosis via its ability to bind to anti-apoptotic genes, and change the expression of anti-apoptis protiens , like Bcl-2, Bcl-XL, and IAPs family [18].…”

Apigenin: A current review on its beneficial biological activities

“…Apigenin has cytostatic and cytotoxic effects on various cancer cells at different doses (Table ), including pancreatic cancer BxPC‐3, PANC‐1, AsPc‐1, Panc‐1, and MiaPaCa‐2 cells (Johnson & de Mejia, ; Wu et al, ); prostate cancer DU145, LNCaP, and PC‐3 cells (Oishi et al, ; Shukla, Fu, & Gupta, ); breast cancer MDA‐MB‐231, MDA‐MB‐453, MBA‐MB‐468, MCF‐7, MCF‐10A, and SK‐BR‐3 cells (Bai, Jin, Yang, Zhu, & Cai, ; Harrison, Coombs, Delaney, & Hoskin, ; Seo et al, ); ovarian cancer SKOV3 cell (Suh, Jo, Lee, & Lee, ); cervical cancer HeLa, CaSki, and C33A cells (Oh et al, ; Zheng, Chiang, & Lin, ); lung cancer H1299, H460, and H2030 cells (Lee et al, ); glioma and glioblastoma C6, U251, and GL‐15 cells (Santos et al, ; Wang et al, ); osteosarcoma U2OS and MG63 cells (Liu et al, ); papillary thyroid carcinoma BCPAP cell (Zhang et al, ); bladder cancer T‐24 cell (Shi, Shiao, Lee, & Shih, ); colorectal cancer cells (Xu et al, ); and leukemia cells (Ruela‐de‐Sousa et al, ). The antitumor effect of apigenin has also been validated in vivo experiments, indicating that it can significantly prolong the survival time and suppress the tumor growth (Chen, Landis‐Piwowar, Chen, & Dou, ; Shukla et al, ).…”

“…The antitumor effect of apigenin may result from a complex interplay. Many data have shown that apigenin may block the phosphorylation and degradation of IκB α by inhibiting IKK activation, which in turn lead to the suppression of nuclear factor (NF)‐κB activation and subsequent downregulation of NF‐κB‐mediated genes involved in the proliferation (cyclin D1 and cyclooxygenase‐2 [COX‐2]), anti‐apoptosis (Bcl‐2 and Bcl‐xL), and angiogenesis (vascular endothelial growth factor [VEGF] of cancer cells) (Johnson & de Mejia, ; Seo et al, ; Shukla et al, ; Wang et al, ; Wu et al, ). Apigenin may also decrease the levels of cyclin A, cyclin B1, cyclin E, CDK2, Cdc2, and Cdc25C to block the cell cycle progression (subG1 phase accumulation), and increase the levels of Bax, Bad, Bak, caspase‐3, caspase‐7, and caspase‐9 to strengthen the caspase‐dependent apoptosis in human bladder cancer T‐24 cell (Shi et al, ).…”