Abstract
Research over the years has progressively shown substantial broadening of the tumor necrosis factor alpha- related apoptosis-inducing ligand (TRAIL)-mediated signaling landscape. Increasingly it is being realized that pancreatic cancer is a multifaceted and genomically complex disease. Suppression of tumor suppressors, overexpression of oncogenes, epigenetic silencing, and loss of apoptosis are some of the extensively studied underlying mechanisms. Rapidly accumulating in vitro and in vivo evidence has started to shed light on the resistance mechanisms in pancreatic cancer cells. More interestingly a recent research has opened new horizons of miRNA regulation by DR5 in pancreatic cancer cells. It has been shown that DR5 interacts with the core microprocessor components Drosha and DGCR8, thus impairing processing of primary let-7. Xenografting DR5 silenced pancreatic cancer cells in SCID-mice indicated that there was notable suppression of tumor growth. There is a paradigm shift in our current understanding of TRAIL mediated signaling in pancreatic cancer cells that is now adding new layers of concepts into the existing scientific evidence. In this review we have attempted to provide an overview of recent advances in TRAIL mediated signaling in pancreatic cancer as evidenced byfindings of in vitro and in vivo analyses. Furthermore, we discuss nanotechnological advances with emphasis on PEG-TRAIL and four-arm PEG cross-linked hyaluronic acid (HA) hydrogels to improve availability of TRAIL at target sites.
Highlights
Multifaceted mechanisms including crosstalk of signaling pathways, genetic/epigenetic mutations, inactivation of tumor suppressors and activation of oncogenes in pancreatic cancer have gained tremendous appreciation in the past decade (Diamantidis et al, 2008)
It is surprising to note that intrinsic pathway is triggered via an additional amplification loop that involves the cleavage of Bid by caspase-8 to truncated Bid. tBid moves into the mitochondrion to facilitate release of cytochrome c
It has recently been shown that a multipronged approach, consisting of atorvastatin, celecoxib and tipifarnib considerably reduced growth of the tumors in SCID mice xenografted with pancreatic cancer cells (Ding et al, 2014)
Summary
Multifaceted mechanisms including crosstalk of signaling pathways, genetic/epigenetic mutations, inactivation of tumor suppressors and activation of oncogenes in pancreatic cancer have gained tremendous appreciation in the past decade (Diamantidis et al, 2008). Bax and Bak are in an inactive state at the outer mitochondrial membrane upon stimulation, pro-apoptotic proteins including Puma or Bim trigger activation of Bax and Bak via dissociation from anti-apoptotic Bcl-2 family. It has previously been convincingly revealed using pancreatic cancer cell lines differentially expressingBclXL that TRAIL induced apoptosis was impaired in Bcl-XL overexpressing cancer cell lines (Panc-1 and PancTuI). It is noteworthy that actinomycin improved TRAIL induced apoptosis in resistant cancer cells via targeting of cFLIP (Matsuzaki et al, 2001) Another contemporary study indicated that differentially high levels of decoy receptors inhibited an efficient TRAIL induced apoptosis (Ibrahim et al, 2001). There was a marked increase in expression of Smac/DIABLO and cytochrome C (Zhao et al, 2011)
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