Abstract LB-101: Lycopene suppresses the NF-κB signaling pathway through inhibition of IκB kinase in human prostate cancer cells
Authors: Emelia A. Assar, Mridula Chopra, Sassan Hafizi
Journal: Cancer Research (2015)

Abstract Prostate cancer is the fourth most common cancer worldwide and the second most common amongst American men. Alongside age and genetic factors, lifestyle and diet have also been implicated as significant factors involved in the pathology of cancer and prostate cancer risk. The tomato-derived antioxidant lycopene has been highlighted as a key protective nutrient amongst various dietary components, with several in vitro studies having reported anti-cancer properties. However, the mechanism of action of lycopene is not fully characterized. We present here a comprehensive investigation of the influence of lycopene on the cell signaling pathway regulating nuclear factor kappa B (NF-κB). NF-κB is a redox-sensitive transcription factor that is believed to play a critical role in the development of the cancer phenotype in cells and has been linked to the early onset and progression of prostate cancer. Phosphorylation of IκB releases NF-κB from sequestration in the cytoplasm, allowing its translocation into the nucleus and consequent tumorigenic gene expression. We studied the effect of lycopene in vitro on multiple points along the NF-κB signaling pathway in two highly malignant, androgen-independent prostate cancer cell lines, DU145 and PC3. Lycopene (0.5-5 μM) was incubated with the cells for 48h, and significantly inhibited prostate cancer cell growth in a formazan cell growth assay at physiologically relevant concentrations of ≥1.25 μM. Similar concentrations of lycopene also caused 30-40% reduction in levels of both basal and TNF-stimulated IκB phosphorylation in cultured DU145 and PC3 cells after 20h, as determined by western blotting. Furthermore, the same degree of inhibition by lycopene was observed for NF-κB transcriptional activity in both cell lines, as determined by a reporter gene assay. NF-κB transcriptional activity in DU145 and PC3 cells was suppressed by 20-40% (p&amp;lt;0.05) and 20-50% (p&amp;lt;0.001) respectively. Further probing of lycopene's effects on upstream elements of the NF-κB pathway showed a significant inhibition of both activity of recombinant IKKβ kinase in a cell-free in vitro assay by approximately 25% (p&amp;lt;0.01), as well as activity of IKKβ immunoprecipitated from cells treated with lycopene. In conclusion, our findings show that the anti-cancer properties of lycopene may occur through its inhibition of the NF-κB signaling pathway, beginning at the early stage of IKK kinase activity. Furthermore, these effects in prostate cancer cells were observed at concentrations of lycopene that are physiologically relevant and achievable in man. Ongoing work is exploring the mechanisms behind the redox regulation of IKK activity by lycopene, as well as the downstream genes regulated by its control of NF-κB signaling. Unraveling the mechanisms by which lycopene acts as an anti-cancer nutritional agent has implications for the control of prostate cancer development through diet. Citation Format: Emelia A. Assar, Mridula Chopra, Sassan Hafizi. Lycopene suppresses the NF-κB signaling pathway through inhibition of IκB kinase in human prostate cancer cells. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr LB-101. doi:10.1158/1538-7445.AM2015-LB-101