Regulators of TRAIL resistance in normal and transformed cells
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TRAIL is a member of the Tumor Necrosis Factor superfamily which was shown to be able to induce apoptotic cell death in a wide variety of transformed cells, leaving normal, healthy cells unharmed. However, approximately 50-60% of the cancer cells were shown to be resistant to the cytotoxic effect of TRAIL, a large number of chemotherapeutics are being studied to broaden the efficacy of TRAIL. However the effect of these co-treatments on non-transformed cells is unpredictable as at present we do not have a proper understanding on the regulation behind the resistance of normal cells to TRAIL. Preliminary works in our lab showed that in primary non-transformed cells TRAIL resistance is maintained by multiple anti-apoptotic proteins. In order to overcome the resistance toward TRAIL-induced apoptosis, the pathway has to be inhibited at two different stages by removal of anti-apoptotic proteins (cFLIP, Mcl-1, Bcl-2, Bcl-XL or XIAP). Using different transcription site searches we have identified the transcription factor Sp1 as a candidate for maintaining the expression levels of these anti-apoptotic proteins, which in turn is regulated by the activity of GSK3 and CDK1. In contrast to the observed redundancy in resistance mechanism to TRAIL seen in non-transformed cell lines, the majority of the cancer cell lines tend to rely on a single mechanism of resistance against TRAIL. This redundancy in TRAIL resistance in non-transformed cells indicate that there is a safe therapeutic window using TRAIL-based combination therapies, which targets a single, dominating resistance pathway. However knowledge of the mechanism of resistance should aid the choice of therapy. TRAIL also activates non-apoptotic/inflammatory signaling, such as the NF-kappaB pathway which in certain cases may drive the resistance to TRAIL. In order to examine the involvement of this non-apoptotic pathway in TRAIL signaling, a reliable inhibitor would be needed that is able to uncouple the death ligand-mediated canonical NF-kappaB activation from apoptosis signaling. Using computer-aided drug design we have performed several virtual screening methods to identify lead molecules that would be able to break up the interaction between TRADD and TRAF2 and thus selectively block death receptor induced NF-kappaB activation.