There is persuasive epidemiological evidence that consumption of dietary polyphenolic plant-derived compounds reduce chronic disease such as cancer. Many laboratory studies including us have shown the inhibitory effect of dietary compounds including resveratrol, genistein, and diaryl disulfide against carcinogenesis in vivo and in vitro. Green tea and its constituent polyphenols (catechins) have been shown to possess anti-tumor properties in a wide variety of experimental systems. Some reports are suggesting an involvement of p53 tumor suppressor proteins, but others do not. Thus, the exact molecular mechanism by which green tea induce anti-tumorigenic effect is not clear. One promising mechanism is the induction of apoptosis by catechins. Indeed, catechins have been known to be associated with the induction of apoptosis. In this regard, our hypothesis of this novel proposal is that the cancer chemopreventive effect of green tea components including catechin (-) epigallocatechin 3-gallate (EGCG), epicatechin gallate (ECG), epigallocatechin (EGC), and epicatechin (EC) is through the induction of apoptotic mechanisms involving the induction of a newly identified TGF-beta superfamily protein, NAG-1 (Nonsteroidal anti-inflammatory drug activated gene). The rationale for this hypothesis is based on the followings: 1) identification of the NAG-1 gene as a dietary induced gene, 2) higher NAG-1 expression in normal colonic epithelial than adjacent tumor cells, 3) NAG-1 has pro-apoptotic and anti-tumorigenic activities reported by us and other groups. Therefore, the overall goal of this project is to identify single catechins or the combinations of catechins for higher NGA-1 inducer in human colorectal cancer cells. To investigate the molecular mechanisms of which a green tea component or combination of them induces NAG-1 expression, we will use two different models, HCT- 116 human colorectal adenocarcinoma cells and mouse model system with following specific aims: 1. Define transcriptional regulatory mechanisms responsible for NAG-1 induction by ECG and other catechins. 2. Profile changes in gene expression following ECG treatment. 3. Compare the preventative and therapeutic efficacy of individual and combination catechins in animal models of colorectal cancer.
