TRAIL resistance results in cancer progression: a TRAIL to perdition?

Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL, APO-2L) is a mediator of cell death that preferentially targets cancer cells. The potential of TRAIL as a chemotherapeutic agent is limited, however, because of the emergence of TRAIL resistance. Furthermore, recent studies have demonstrated that alternative TRAIL signaling is unmasked in TRAIL resistant cells. In these cells, the predominant effect of TRAIL receptor activation is the activation of nuclear factor-kappaB (NF-kappaB), which promotes tumor metastases and invasion. TRAIL resistance can occur at the level of the death inducing signaling complex via upregulation of cFLIP or via an increase in antiapoptotic proteins of the Bcl-2 family. A paradigm emerges from this information, that chemotherapy, targeting NF-kappaB, cFLIP, or antiapoptotic proteins of the Bcl-2 family, in combination with TRAIL maybe more rational than TRAIL therapy alone.