Decoy receptors one and 2, equivalent to TRAIL R1 and TRAIL R2, are expressed to the cell surface. As a result, overexpression of either DcR1 or DcR2 confers safety against TRAIL induced apoptosis, The fifth TRAIL receptor is osteoprotegerin, a secreted, reduced affinity receptor for TRAIL, Binding of TRAIL to TRAIL R1 and TRAIL R2 induces trimerization of TRAIL R1 and TRAIL R2, The trimerized TRAIL R1 and TRAIL R2 bind to FADD, which recruits caspase eight and initiates a proteolysis cas cade that at some point contributes to cell death by apoptosis.
Several cancer cells are resistant to death receptor induced apoptosis, The mechanisms of resistance incorporate the presence of decoy receptors for TRAIL, the loss of TRAIL receptor expression, the overexpression of inhibitory proteins in signal transduction pathways for example FLICE inhibitory protein, plus the mutation of TRAIL R2 selleck mapk inhibitor gene, Oncogenic mutations for instance ras may enrich expres sion of TRAIL receptors, possibly sensitizing these tumors to TRAIL based mostly therapies, Constitutively activated Ras increases the tumorigenic possible of cells because it causes deregulation of essential intracellular signaling pathways, Activated RAS mediates its bio logical action as a result of interaction with numerous down stream effector targets, thus activating pathways like MEK, PI3K, and Rho GTPases, RAS regulates a RAF MEK ERK1 2 kinase cascade and this pathway is observed for being active in human colon adenocarcinomas cells also as in human colorectal tumors, Drosopoulos et al. have proven transformation from the colon cell line Caco 2 by ras oncogenes sensitizes spe cific MEK dependent up regulation of TRAIL R1 and TRAIL R2. Nesterov A et al. have demonstrated that typical cells are sensitized to TRAIL when TRAIL R2 is up regulated by overexpression of c myc or onco genic ras mutants.
Therefore, RAS MEK ERK1 two signaling pathway can sensitize cells to TRAIL induced apoptosis by up regulating TRAIL R1, TRAIL R2 and TRAIL based therapeutic strategies using TRAIL agonists could be utilised in situations of human colon cancers bearing RAS mutations. Hence, we also sought to investigate the likely Perifosine website link concerning expression of TRAIL and its receptors with KRAS alterations in CRC. The aims of the present review had been. to find out the TRAIL TRAIL receptor expression pattern in nor mal and neoplastic colon epithelium, to correlate immunohistochemical expression patterns with KRAS alterations, microsatellite instability and professional apoptotic markers, to correlate immunohistochemical expres sion patterns with general survival.