Two death-inducing human TRAIL receptors to target in cancer: similar or distinct regulation and function?

The emergence during evolution of two tumour necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) receptors, receptor-1/DR4 and -2/DR5, able to induce apoptosis has raised the question whether they differ in function and regulation, which is of key importance for selecting either DR4 or DR5 selective pro-apoptotic agents for cancer treatment. In this review we found practically no information regarding possible differences in DR4 and DR5 function based on structural differences. On the other hand, a panel of different DR4 or DR5 selective pro-apoptotic agonists have been developed that were explored for efficacy in different tumour types in a large number of studies. Leukemic cells appear mainly sensitive for DR4-induced apoptosis, contrasting the situation in other tumour types that show heterogeneity in receptor preference and, in some cases, a slight overall preference for DR5. Both receptors were found to mediate intracellular stress-induced apoptosis, although this is most frequently reported for DR5. Interestingly, DR5 was also found to transmit non-apoptotic signalling in resistant tumour cells and recently nuclear localization and a role in microRNA maturation has been described. DR4 expression is most heavily regulated by promoter methylation, intracellular trafficking and post-translational modifications. DR5 expression is predominantly regulated at the transcriptional level, which may reflect its ability to respond to cellular stressors. It will be important to further increase our understanding of the mechanisms determining TRAIL receptor preference in order to select the appropriate TRAIL receptor selective agonists for therapy, and to develop novel strategies to enhance apoptosis activation in tumours.