Ionizing Radiation Induction of Apoptosis in TRAIL Resistant Cancer Cells

TRAIL mediated signaling has gained tremendous appreciation because of its ability to selectively induce apoptosis in cancer cells and leaving non-cancer cells intact. Data obtained through increasingly sophisticated laboratory methodologies, is deepening our understanding about intracellular signaling modulators of TRAIL. It is now well established that there are wide ranging regulators of TRAIL mediated signaling cascade. However there was a paradigm shift in the research trends when it was reported continuously by various research groups that different cancer cells were resistant to TRAIL induced apoptosis. In vitro analysis and gene silencing strategies helped in expanding the signaling landscape. TRAIL induced apoptosis in cancer cells via Death receptors DR4 and DR5. There are two well studied pathways through which TRAIL induced apoptosis including extrinsic pathway and intrinsic pathway. Research over the years has provided exciting pieces of evidence which describe various steps of TRAIL mediated signaling. Binding of TRAIL to TRAIL receptor (DR4 or DR5) resulted in receptor oligomerization. Later, Death receptor, FADD and Pro-caspase-8 together form Death Inducing Signaling Complex (DISC). However, cFLIP is an anti-apoptotic protein and has two death-effector domains (DEDs). cFLIP negatively regulates TRAIL induced signaling by interfering with the activation of