Marine Drugs: Modulation of TRAIL Induced Apoptosis in Cancer Cells

Cancer is a multifaceted and genomically complex disease. Research over decades has shown involvement of different biological mechanisms including suppression of tumor suppressor genes, overexpression of oncogenes, genetic/epigenetic mutations, intra-tumor heterogeneity, genomic instability and loss of apoptotic signaling network that signals through membrane death receptor-mediated intracellular cascade. Accumulating experimentally verified evidence is providing in-depth analysis of molecular mechanisms of common signaling nodes, pathway crosstalk and the role of multi-functional proteins in regulation of cell death. Biochemical and structural biological studies have shown that tumor necrosis factor-related apoptosisinducing ligand (TRAIL) signals through death receptors which possess a cytoplasmic death domain (DD) and belong to tumor necrosis factor receptor superfamily. TRAIL discovery revolutionized the field of molecular oncology and attracted researchers world-wide to unravel the signal transduction machinery triggered by this ligand. Adaptor protein Fas-associated death domain (FADD) is positioned at Death Receptor and forms a signalosome termed as death-inducing signaling complex (DISC) . DISC consisting of FADD and Pro-caspase-8 is formed at the death receptor and is negatively regulation by its key inhibitor c-FLIP, has been extensively investigated. Downstream from DISC, the apoptotic signals are transduced through two deeply studied pathways including extrinsic and intrinsic pathway. Caspase-8 activates its