The pro-survival effect is associated with an increased expression of the inhibitor of apoptosis protein-1 (c-IAP1), a decrease of TRAIL-induced cleavage of PARP, procaspase 9 and procaspase 3, and a decrease of cytochrome C release from the mitochondria.
In addition, the comparison between normal and tumour tissue illustrated a significant decrease of TRAIL-β mRNA levels in gastric carcinomas.
Furthermore, knockdown of TRAIL-R2 resulted in decreased growth of experimental orthotopic tumors in mice, and progressive decrease of TRAIL-R2 expression as well as its exclusion from the nuclei accompanied the differentiation of pancreatic tumor cells into three-dimensional duct-like structures in vitro.
Differentiating NHEKs, however, displayed decreased expression of TRAIL receptors and TRAIL-induced apoptosis.
Since a decrease of synthesized TRAIL-γ transcripts could permit an increase of transcribed and finally translated proapoptotic TRAIL-α, this could also explain our observation that downregulation of TRAIL-γ was associated with a worse prognosis.
The low or absent levels of HIF-2α decrease the levels of TRAIL receptor DR5 mRNA and protein, explaining the loss of sensitivity.
The major finding of this study is the demonstration that the decreased serum levels of TRAIL, measured within 24 hours after AMI (baseline), were inversely correlated with important prognostic markers for adverse cardiovascular events, such as circulating levels of CK, CK-MB and BNP.
Knock down of the HIF-2α protein by RNA interference (short hairpin RNA) blocked TRAIL-induced apoptosis, decreased the level of TRAIL receptor (DR5) protein and inhibited the transcription of DR5 messenger RNA.
Furthermore, differentiating keratinocytes displayed decreased membrane expression of TRAIL receptors 1 and 2. However, AhR agonists did not affect expression of these receptors in both HaCaT cells and dividing keratinocytes, thus excluding altered receptor levels as putative mechanism (Supplementary Figure 3).
Furthermore, the shIPS-1 cells showed a significant decrease in the levels of TRAIL expression and in contrast, BCL2 and PRKCE were modestly upregulated, but the expression of BIRC3 remained unchanged (Supplementary Figure S2).
