Figure 1.

(a) Representation of the TRAIL-resistant phenotype exhibited by TrkA SH-SY5Y NB cells in the absence of NGF, demonstrating cFLIP-mediated inhibition of TRAIL-induced pro-caspase-8 activation, absence of Bid cleavage, maintenance of mitochondrial integrity and optimised X-linked inhibitor of apoptosis (XIAP)-mediated blockage of pro-caspase-9 and pro-caspase-3 activation, combining to result in TRAIL resistance. (b) Representation of NGF sensitisation of TRAIL-resistant TrkA SH-SY5Y NB cells to TRAIL-induced apoptosis, demonstrating cFLIP sequestration by NGF-activated TrkA, TRAIL-induced activation of pro-caspase-8 and subsequent Bid cleavage (tBid), tBid induction of mitochondrial outer membrane permeabilisation, subsequent release to the cytoplasm of mitochondrial components (Omi/Smac/Cyto c), leading to compromised XIAP function, facilitating cytochrome c-mediated activation of pro-caspase-9 and pro-caspase-3, resulting in the induction of type II apoptosis through the intrinsic mitochondrial pathway. NGF stimulation of Mcl-1 expression through NF-κB, responsible for the eventual blockage of the temporary NGF-sensitisation response, and relief of this blockage by Mcl-1 siRNA and dominant negative dn-NF-κB are also shown