Mechanisms of resistance of normal cells to TRAIL induced apoptosis vary between different cell types

Abstract

Resistance of normal cells to tumour necrosis factor related apoptosis inducing ligand (TRAIL) induced apoptosis is believed to be mediated by expression of two decoy receptors. Here we show that the expression and localisation of TRAIL receptors (TRAIL-Rs) vary between different cells and that resistance to TRAIL is mediated by different mechanisms. The decoy receptor, TRAIL-R3, appeared important in protection of endothelial cells, whereas lack of surface death receptor expression and as yet unknown intracellular inhibitor(s) of apoptosis downstream of caspase-3 may play a major role in protection of melanocytes and fibroblasts from TRAIL induced apoptosis, respectively. Differential subcellular location of decoy receptors may be an important determinant of their effectiveness in different types of normal cells. ß

TNF-Related Apoptosis-Inducing Ligand Death Pathway-Mediated Human Beta-Cell Destruction

“…If this is true, then negative TRAIL expression in CM cells in RT-PCR assays might explain their susceptibility to the TRAIL death pathway. Normal islet cells show susceptibility to the TRAIL death pathway after treatment by PI-PLC, consistent with a similar study using human normal umbilical vein endothelial cells as TRAIL target cells [40]. Treatment with PI-PLC could remove the TRAIL-R3 receptors from the cell membrane [11,40].…”

“…We have shown in this study that TRAIL-R1, -R2, -R3 and/or -R4 mRNA is expressed in normal primary TRAIL can induce apoptosis in a wide range of transformed cell lines but not in many normal cells, although the mRNAs of TRAIL-R1 and R2 were found to be widely expressed on normal tissue [40]. Similarly, most of the normal islet cells in this study are resistant to the TRAIL death pathway, although these cells express TRAIL receptors R1 and R2.…”

“…Similarly, most of the normal islet cells in this study are resistant to the TRAIL death pathway, although these cells express TRAIL receptors R1 and R2. Many factors might influence the susceptibility and resistance of normal islet cells to the TRAIL pathway [40]. The normal tissue cells are believed to be protected from apoptosis by the two additional decoy receptors, TRAIL-R3 and -R4.…”

Mechanisms involved in development of resistance to adenovirus-mediated proapoptotic gene therapy in DLD1 human colon cancer cell line

“…Both recombinant, soluble TRAIL and wild-type, membrane-bound TRAIL induce apoptosis in a wide variety of transformed cell lines via interaction with one or both of the death receptors DR4/TRAIL-R1 and DR5/TRAIL-R2, 12,13 which in turn initiates activation of caspase-8 through FADD, leading to apoptosis. [14][15][16] However, the antagonistic decoy receptors DcR1, 17,18 DcR2, 19 and osteoprotegerin 20 are believed to protect normal cells from the cytotoxic effects of TRAIL by competing with DR4/TRAIL-R1 and DR5/TRAIL-R2 for TRAIL binding.…”

Green tea polyphenol EGCG sensitizes human prostate carcinoma LNCaP cells to TRAIL-mediated apoptosis and synergistically inhibits biomarkers associated with angiogenesis and metastasis

“…Tumor necrosis factor (TNF)-a-related apoptosisinducing ligand (TRAIL), is a cytokine of TNF family and is capable of inducing apoptotic cell death in a variety of cancer type, while producing negligible effects on normal cells (Zhang et al, 2000;Ozawa et al, 2001;He et al, 2004). Studies have shown that some cancer cells are resistant to the apoptotic effects of TRAIL (Deeb et al, 2004;Yamaguchi et al, 2005;Hu et al, 2006), however, these cells can be sensitized by combination of TRAIL with different chemotherapeutic drugs, indicating that combinatorial approach can be utilized to overcome the resistance of cancer cells to TRAIL.…”