Tumor Necrosis Factor-Related Apoptosis-Inducing Ligand Induces Autophagic Protein Cleavage in Melanoma Cells

Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a naturally occurring protein molecule in humans. Previous studies established that TRAIL is capable of inducing apoptosis of cells which express its cognate surface receptors. It is also known that TRAIL toxicity is specific for cancerous cells but not for normal ones. This has led to the development of TRAIL-derived drugs such as soluble recombinant TRAIL for the purpose of cancer treatment. However, resistance to TRAIL has also been reported in various cancer types including melanoma, a malignant tumor notorious for its resistance to therapies. In our research on the arginine-deprivation treatment for melanoma, we found that TRAIL can be synergistic with arginine depletion in causing cell death through apoptosis, and further investigations revealed that the cleavage of autophagic proteins such as Beclin-1 and Atg5 played an important part in switching autophagy toward apoptosis in melanoma cells. In this chapter, a more comprehensive review on TRAIL-induced cleavage of autophagic proteins in melanoma and relevant results from other types of cancers are discussed. The purpose of this review is to shed more light on the significance of this transition from autophagy to apoptosis through autophagic protein cleavage. These findings could be applied to the treatment of melanoma and other suitable cancers which use autophagy for survival after anticancer therapies.