TRAIL mediated signaling as a double-edged sword in pancreatic cancer: Analysis of brighter and darker sides of the pathway

Genetic, genomic and proteomic studies have refined our concepts related to underlying mechanisms of pancreatic cancer. Increasingly sophisticated knowledge has started to shed light on the fact that pancreatic cancer harbored multiple epigenetic and genetic alterations and revealed complicated and dense tumor tnicroenvironments. Our rapidly evolving knowledge about pancreatic cancer has helped us in identification of myriad of underlying mechanisms which play instrumental role in disease onset, drug resistance and epithelial to mesenchymal transition (EMT). Additionally, loss of apoptosis is the cornerstone of cancer biology and researchers have devoted considerable attention to the versatile regulators involved in loss and restoration of apoptosis. Discovery of TNF/TNFR, FasL/Fas and TRAIL TRAIL-R opened new horizons for detailed analysis of intracellular mechanisms regulated by these pro-apoptotic molecules. Decades of cutting-edge research helped in translation of TRAIL-based therapeutics into clinically effective therapeutics. In this review, we will focus specifically on groundbreaking achievements which have leveraged our concepts related to TRAIL-mediated signaling to yet another level. We will also discuss how basic and clinical scientists are making efforts to overcome the stumbling blocks associated with efficacy of TRAIL-based therapeutics against TRAIL-resistant pancreatic cancers. We partition this multi-component review into overview of the conceptual breakthroughs in regulation of TRAIL-mediated signaling in pancreatic cancers, push and pull between pro- and anti-apoptotic proteins to regulate TRAIL-mediated apoptosis and how researchers have identified different natural and synthetic molecules to restore apoptosis in TRAIL-resistant pancreatic cancer. We have also summarized how long non-coding RNAs (IncRNAs) and microRNAs (miRNAs) regulated TRAIL-mediated apoptosis in pancreatic cancer. More importantly we will also set spotlight on the darker side of TRAIL/TRAIL-R pathway in pancreatic cancer. Circumstantial evidence highlighted cancer promoting role of TRAIL/TRAIL-R in pancreatic cancer. These diametrically opposed context-dependent roles of TRAIL-pathway are intriguing and need comprehensive research to address outstanding questions.