Epidemiological studies have suggested that lower incidence of prostate cancer could be due to environmental factors, particularly dietary. Consumption of fruits and vegetables, which provides several classes of compounds, including indole-3- carbinol (I3C), may have a protective effect against the development of human prostate cancer. Despite the importance of I3C, knowledge on the molecular mechanism(s) of action of I3C in vitro and in vivo, and its anti-tumor activity against prostate cancer is lacking. Our preliminary results show that, for prostate cancer cells in culture, I3C and its in vivo dimeric product, Diindolylmethane (DIM) inhibits cell proliferation with a concomitant increase in apoptotic cell death by their pleitropic effects on several cell cycle and apoptosis related proteins. Most importantly, we observed inactivation of Akt and NF-kappaB signaling pathway by I3C/DIM in prostate cancer cells but not in non-tumorigenic prostate epithelial cells. Based on these preliminary results, we hypothesize that I3C and DIM (I3C/DIM) function as an inhibitor of Akt, leading to the inactivation of NF-kappaB, which in turn, causes cell growth inhibition and induction of apoptosis. We further hypothesize that I3C/DIM inhibits metastatic prostate tumor growth in experimental bone metastasis model in SCID mice, and that the animal tumors exposed to DIM will lead to alterations in the expression of specific genes, which will be the in vivo molecular targets of I3C/DIM in the processes of prostate cancer metastases. To test our hypotheses, we propose four specific aims.
In aim -1, we will determine whether treatment of non-tumorigenic and tumorigenic prostate epithelial cells with I3C/DIM inactivates the NF-kappaB pathway to the same or different degrees, and (b) investigate the mechanism(s) of NF-kappaB inactivation by measuring phosphorylation and ubiquitination of IkappaB and inhibition in the nuclear translocation of NF-kappaB using confocal microscopy, and correlate these results with apoptotic cell death.
In aim -2, we will investigate the mechanism(s) by which Akt inactivation leads to the down regulation of NF-kappaB by investigating cell signaling molecules that are important regulators of NF-kappaB such as MEKK1, MEK, NIK and IKK using gene transfection studies. These investigations will determine the cause and effect relationships between these signaling molecules and I3C/DIM induced apoptotic cell death in prostate cancer cells.
In aim -3, we will conduct dietary intervention experiments using DIM in Hu-SCID model of human prostate cancer induced by PC-3 human prostate cancer cells. Finally, in aim-4, we will identify gene expression profiles of DIM treated PCa obtained from our Aim-3 using DNA Microarray by interrogating 22, 215 genes (Hu-133A Chip, Affymetrix). These results will be correlated with other molecular targets identified during our preliminary studies using I3C/DIM in cultured PC-3 cells, and also several targets as described under specific aim-2. Collectively, these results will help to identify a comprehensive molecular targets profile of I3C/DIM in prostate cancer that could be further exploited for devising relevant targeted therapy for the prevention and/or treatment of prostate cancer and its metastasis in the future.
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