Abstract

TRAIL (Tumour-Necrosis-Factor related apoptosis-inducing ligand) induces apoptosis by binding to the death receptors DR4 and DR5. Recombinant TRAIL or agonist antibodies against TRAIL death-receptors are now in Phase I/II clinical trials. Despite specificity for cancer cells, a percentage of tumour cells remain insensitive to TRAIL-induced apoptosis. Previous work has demonstrated that signalling through PI3K (phosphatidylinositol-3-kinase) can prevent TRAIL-induced apoptosis in different cancer cell types. Moreover inhibition of HSP90 (Heat Shock Protein 90) by 17-AAG can sensitise colon cancer cells to TRAIL-induced apoptosis.

The aim of this project is to explore the mechanism of TRAIL resistance and to focus on the role of PI3K and HSP90 signalling and the ability of PI3K or HSP90 inhibitors to reverse resistance to TRAIL-induced apoptosis in human colon cancer cells. We demonstrated that co-treatments with TRAIL and PI-103, a PI3K inhibitor, or 17-AAG, an HSP90 inhibitor, synergistically contributed to the apoptotic stimulus in TRAIL sensitive and resistant colon cancer cells through activation of both extrinsic and intrinsic apoptotic pathways.