How melanoma cells evade trail-induced apoptosis

Several natural defence mechanisms kill melanoma cells by apoptosis. These are induced by granzyme B or interaction with members of the tumour necrosis factor (TNF) family, such as TNF-related apoptosis-inducing ligand (TRAIL). As a consequence, melanoma cells that survive in the host might do so because they have been selected for resistance to apoptosis. Resistance mechanisms include low death-receptor expression and inhibition of intracellular death pathways. Induction of p53 is important in upregulation of TRAIL death receptors in response to DNA damage, but relatively little is known about the control of constitutive expression. Fresh isolates of melanoma cells have low death-receptor expression and development of treatments that increase their expression are crucial for the success of TRAIL-dependent killing of melanoma. One of the main inhibitors of TRAIL-induced apoptosis is the inhibitors of apoptosis (IAP) family, particularly XIAP. XIAP levels are reduced after exposure to TRAIL because TRAIL induces release of a pro-apoptotic protein, SMAC/DIABLO, from mitochondria, which binds to and inactivates members of the IAP family. This represents an alternative to the classical mitochondrial death pathway, which is limited in most melanoma cells by low or absent APAF1 levels. SMAC/DIABLO release from the mitochondria of TRAIL-resistant melanoma cells is decreased, possibly due to stabilization of mitochondrial permeability by the BCL2 family. The transcription factor NF-κB and the mitogen-activated protein kinase (MAPK) and extracellular-regulated kinase (ERK) 1 and 2 pathways seem to be the principal regulators of the IAP and BCL2 family, respectively. These findings provide insights into resistance of melanoma to apoptosis and provide a framework for therapeutic approaches based on providing pro-apoptotic stimuli, as well as reducing anti-apoptotic mechanisms.