Intracellular localization of DR5 and related regulatory pathways as a mechanism of resistance to TRAIL in cancer

Abstract

TNF-related apoptosis-inducing ligand (TRAIL) is a prominent cytokine capable of inducing apoptosis. It can bind to five different cognate receptors, through which diverse intracellular pathways can be activated. TRAIL's ability to preferentially kill transformed cells makes it a promising potential weapon for targeted tumor therapy. However, recognition of several resistance mechanisms to TRAIL-induced apoptosis has indicated that a thorough understanding of the details of TRAIL biology is still essential before this weapon can be confidently unleashed. Critical to this aim is revealing the functions and regulation mechanisms of TRAIL's potent death receptor DR5. Although expression and signaling mechanisms of DR5 have been extensively studied, other aspects, such as its subcellular localization, non-signaling functions, and regulation of its membrane transport, have only recently attracted attention. Here, we discuss different aspects of TRAIL/DR5 biology, with a particular emphasis on the factors that seem to influence the cell surface expression pattern of DR5, along with factors that lead to its nuclear localization. Disturbance of this balance apparently affects the sensitivity of cancer cells to TRAIL-mediated apoptosis, thus constituting an eligible target for potential new therapeutic agents.

Keywords: DR4; DR5 internalization; DR5 nuclear localization; DR5 ubiquitination; HuR; Importin β1; TRAIL resistance; mRNA stabilization.

Fig. 1

DR4 and DR5 transcripts compared. CDS coding sequence, UTR untranslated region, miRDB microRNA Database

Fig. 2

Factors affecting intracellular fate of DR5. Two different routes for the DR5 protein to follow within the cell are: plasma membrane localization via mechanisms still not fully elucidated, and nuclear localization through binding of importin β1. When HuR binds to DR5 mRNA under stress conditions, its translation is suppressed