The major goal of this project is to evaluate the mechanisms of lFN-Beta induced apoptosis in colorectal cancer. The direct anti-proliferative effects of type I interferons on many human tumor cell types are well described and have been demonstrated to be synergistic with conventional chemotherapy agents. We as well as others have demonstrated induction of apoptosis following lFN-Beta treatment. However, little is known concerning molecular biology of this process. We have evaluated this process in vitro and identified mediators of apoptosis which are induced by IFN-Beta. We plan to expand upon these findings and further investigate the mechanisms of IFN-Beta induced apoptosis (Aim 1). We wilt determine the IFN-Beta responsiveness of the Bak and TRIAL promoters (Aim 2). We will evaluate the mechanisms of IFN-Beta resistance (Aim 3) and the synergy between IFN-Beta and 5-Flourouracil (5-FU) (Aim 4). First, we will investigate the mechanisms of IFN-Beta induced apoptosis by analyzing the rote of mediators of apoptosis and IFN-inducible proteins. We hypothesize that the process of IFN-Beta induced apoptosis is dependent upon activation of the TRAIL, IRF-1, and Bak (known mediators of apoptosis) via the Jak-Stat pathway. Secondly, we will investigate the transcriptional regulation of TRAIL and Bak by IFN-Beta. We have demonstrated induction of these apoptotic mediators by lFN-Beta and will investigate the activation of the Bak and TRAIL promoter by IFN-Beta. Thirdly, we will investigate the mechanisms of lFNBeta resistance in colorectal cancer. We hypothesize that resistance in cells develops secondary to the interruption of the JAK-Stat pathway or downstream apoptotic pathways. Finally, we will investigate the mechanisms of synergy between IFN-Beta and 5-FU. We hypothesize that the synergy between IFN-Beta and 5-FU is secondary to an enhanced induction of apoptosis via the Jak-Stat pathway and the subsequent induction of the cell surface and mitochondria apoptotic pathways. The development of criteria predicting the potential effectiveness of interferon therapy would be of high clinical relevance. This information would allow us to spare unnecessary toxicities to non-responders and would contribute to the identification of patient populations who may benefit from this therapy. This process will begin with the discovery of the molecular mechanisms of this process.
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| Lei, Hanqin; Furlong, Patrick J; Ra, Jin Hee et al. (2005) AKT activation and response to interferon-beta in human cancer cells. Cancer Biol Ther 4:709-15 |
| Choi, Eugene A; Lei, Hanqin; Maron, David J et al. (2004) Combined 5-fluorouracil/systemic interferon-beta gene therapy results in long-term survival in mice with established colorectal liver metastases. Clin Cancer Res 10:1535-44 |
| Choi, Eugene A; Lei, Hanqin; Maron, David J et al. (2003) Stat1-dependent induction of tumor necrosis factor-related apoptosis-inducing ligand and the cell-surface death signaling pathway by interferon beta in human cancer cells. Cancer Res 63:5299-307 |
