Background and aims: Prostate cancer is the second most common cancer among men worldwide and the number of new cases is increasing with the increasing life expectancy. The disease is associated with an aberrant upregulation of the transcription factor NF-κB. In previous studies, tomatoes have shown promising results in terms of prevention of prostate cancer, and coffee has been reported to be among the most potent inhibitors of NF-κB. Therefore, this thesis examined the effect of coffee and tomatoes on NF-B and inflammation- and cancer related genes in prostate cancer cells both in vitro and in xenografts, as well as studying the tissue accumulation of tomato constituents.
Methods: The ability of coffee and tomatoes to modulate NF-κB activity was investigated using a prostate cancer (PC3) cell line stably transduced with a luciferase reporter gene coupled to a promoter with NF-κB binding sites. Q-RT-PCR was used to analyse the effect of coffee and tomatoes on expression of genes related to immunity, inflammation and cancer in PC3 cells in culture and in xenografts. Analysis of accumulation of carotenoids in tissue of mice fed a diet enriched with tomato paste was performed using HPLC.
Results: Coffee induced basal NF-κB activity, but inhibited TNF-α induced NF-κB activity in PC3 cells in vitro. In general, the mRNA levels of genes involved in cytoprotection were upregulated, wheras a number of genes related to inflammation, apoptosis and tumor suppression were downregulated in cultured PC3 cells treated with TNF-α and extract of coffee as compared to controls treated with TNF-α only. In xenograft of PC3 cells, genes related to inflammation, apoptosis, cytoprotection and cell proliferation and differentiation were downregulated in mice fed a coffee containing diet. Tomatoes had a strong inhibitory effect on TNF-α induced NF-κB activity in PC3 cells. In TNF- stimulated PC3 cells, genes related to inflammation and tumor suppression were downregulated by tomato extract, whereas genes related to apoptosis and cancer were upregulated. The ability of tomato to modulate the gene expression was less prominent in PC3 xenografts, however, ICAM-1 was upregulated, while the TGFβ1 gene was downregulated. Furthermore, carotenoids accumulated in several tissues, including liver, heart, spleen and seemingly also prostate, in mice fed a diet supplemented with tomato paste.
Conclusions: We found that coffee and tomatoes are strong inhibitors of TNF-α induced NF-κB activity in PC3 cells, and have the ability to modulate a number of genes related to cancer. Furthermore, we found that carotenoids accumulate in tissues of mice fed a diet rich in tomato paste. Our results may support a preventive role of coffee and tomatoes in prostate cancer, and further research should focus on elucidating the mechanisms behind the effects of coffee and tomatoes on NF-κB activity and expression of genes related to prostate cancer.