title: 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.affiliation: Department of Urology, Case Western Reserve University, Cleveland, Ohio, United States of America; The Urology Institute, University Hospitals Case Medical Center, Cleveland, Ohio, United States of America.
authors.forename: Sanjeev
authors.initials: S
authors.lastname: Shukla
authors.affiliation: Department of Urology, Case Western Reserve University, Cleveland, Ohio, United States of America; The Urology Institute, University Hospitals Case Medical Center, Cleveland, Ohio, United States of America.
authors.forename: Eswar
authors.initials: E
authors.lastname: Shankar
authors.affiliation: Department of Epidemiology & Biostatistics, Case Western Reserve University, Cleveland, Ohio, United States of America; Division of General Medical Sciences, Case Comprehensive Cancer Center, Cleveland, Ohio, United States of America.
authors.forename: Pingfu
authors.initials: P
authors.lastname: Fu
authors.affiliation: Department of Pathology, Case Western Reserve University, Cleveland, Ohio, United States of America.
authors.forename: Gregory T
authors.initials: GT
authors.lastname: MacLennan
authors.affiliation: Department of Urology, Case Western Reserve University, Cleveland, Ohio, United States of America; The Urology Institute, University Hospitals Case Medical Center, Cleveland, Ohio, United States of America; Department of Nutrition, Case Western Reserve University, Cleveland, Ohio, United States of America; Division of General Medical Sciences, Case Comprehensive Cancer Center, Cleveland, Ohio, United States of America; Department of Urology, Louis Stokes Cleveland Veterans Affairs Medical Center, Cleveland, Ohio, United States of America.
authors.forename: Sanjay
authors.initials: S
authors.lastname: Gupta
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology; D016588:Anticarcinogenic Agents / Q000494:pharmacology; D047310:Apigenin / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D053148:Caspase 3 / Q000235:genetics; D049109:Cell Proliferation / Q000187:drug effects / Q000235:genetics; D015536:Down-Regulation / Q000187:drug effects / Q000235:genetics; D004789:Enzyme Activation / Q000187:drug effects / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects* / Q000235:genetics; D051550:I-kappa B Kinase / Q000235:genetics*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D016328:NF-kappa B / Q000235:genetics*; D009389:Neovascularization, Pathologic / Q000188:drug therapy / Q000235:genetics; D010766:Phosphorylation / Q000187:drug effects / Q000235:genetics; D011471:Prostatic Neoplasms / Q000188:drug therapy / Q000235:genetics; D015398:Signal Transduction / Q000187:drug effects* / Q000235:genetics; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
chemical_list: D000893:Anti-Inflammatory Agents; D016588:Anticarcinogenic Agents; D016328:NF-kappa B; D042461:Vascular Endothelial Growth Factor A; D047310:Apigenin; D051550:I-kappa B Kinase; D053148:Caspase 3