Lots of cancer cells are resistant to death receptor induced apoptosis, The mechanisms of resistance incorporate the presence of decoy receptors for TRAIL, the reduction of TRAIL receptor expression, the overexpression of inhibitory proteins in signal transduction pathways such as FLICE inhibitory protein, and also the mutation of TRAIL R2 gene, Oncogenic mutations this kind of as ras may perhaps increase expres sion of TRAIL receptors. potentially sensitizing these tumors to TRAIL based therapies, Constitutively activated Ras increases the tumorigenic potential of cells because it causes deregulation of vital intracellular signaling pathways, Activated RAS mediates its bio logical activity via interaction with a variety of 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 identified to be active in human colon adenocarcinomas cells as well as in human colorectal tumors, Drosopoulos et al.
have proven transformation of the colon cell line Caco two by ras oncogenes sensitizes these cells to TRAIL induced apoptosis by triggering spe cific MEK dependent up regulation of TRAIL R1 and TRAIL R2. Nesterov A et al. have demonstrated that regular cells are sensitized to TRAIL when TRAIL R2 is up regulated by overexpression of c myc or onco genic ras mutants. Thus, RAS MEK ERK1 2 signaling pathway can sensitize selelck kinase inhibitor cells to TRAIL induced apoptosis by up regulating TRAIL R1, TRAIL R2 and TRAIL based therapeutic strategies making use of TRAIL agonists may be utilized in instances of human colon cancers bearing RAS mutations. Hence, we also sought to take a look at the prospective hyperlink concerning expression of TRAIL and its receptors with KRAS alterations in CRC. The aims in the existing research have been.
to determine the TRAIL TRAIL receptor expression pattern in nor mal and neoplastic colon epithelium. to correlate immunohistochemical expression patterns with KRAS alterations, microsatellite instability and pro apoptotic markers. to correlate immunohistochemical expres sion patterns with overall survival. Outcomes Expression of TRAIL and its receptors TRAIL R1 and TRAIL R2 Incidence of TRAIL R1, TRAIL R2 and TRAIL ligand selleckchem amn-107 expression in CRC was 85. 5%, 59. 4 and 31. 5% respectively, These inci dences are inside the wide ranges reported earlier TRAIL. 37. 5% to 83%, TRAIL R1.58. 1% to a hundred. 0% and TRAIL R2. 40. 3% to 100%, Incidence of non interpretable tumor spots for TRAIL, TRAIL R1 and TRAIL R2 ranged from ten to 18%. Tumor spots have been deemed not interpretable when they had inadequate tumor cells, loss of tissue within the spot, or an abundance of necrotic tissue.