Abstract
NGF FLIPs TrkA onto the death TRAIL in neuroblastoma cells.
Highlights
TNFR1, FasL, FasR, DR3, DR4 and DR5 death receptors
In our recent Cell Death Discovery publication,[11] we describe a novel nerve growth factor (NGF)-mediated mechanism for sensitising tropomyosin-related kinase A (TrkA)-expressing SH-SY5Y NB cells to TRAIL-induced apoptosis that abrogates anchorage-independent tumorigenic growth in vitro
NGF sensitisation of TrkA-expressing SH-SY5Y NB cells to TRAIL-induced apoptosis was abrogated by TrkA tyrosine kinase and caspase inhibitors, associated with permeabilisation of the outer mitochondrial membrane, increasing cytosolic levels of mitochondrial Omi/Htr2a and cytochrome c, and reducing cytosolic levels of X-linked inhibitor of apoptosis, and was inhibited by ectopic overexpression of B-cell lymphoma extra large (Bcl-xL), confirming that apoptosis was TrkA tyrosine kinase dependent, caspase dependent and mediated through the intrinsic mitochondrial pathway
Summary
TNFR1, FasL, FasR, DR3, DR4 and DR5 death receptors. Among this cytokine family, TRAIL is considered to be a promising chemotherapeutic agent because of its selective pro-apoptotic action on tumour, but not non-transformed cells.[4,5,6] the potential therapeutic application of TRAIL in NB has been hampered by observations of TRAIL resistance in NB models, which has been attributed to caspase-8 silencing, altered decoy and functional TRAIL receptor expression, expression of the cellular FLICE-like inhibitory protein (cFLIP) inhibitory analogue of caspase-8, protective IP3K/Akt/mTor signalling or protective RIP/nuclear factor kappa binding (NF-κB) signalling. In our recent Cell Death Discovery publication,[11] we describe a novel NGF-mediated mechanism for sensitising TrkA-expressing SH-SY5Y NB cells to TRAIL-induced apoptosis that abrogates anchorage-independent tumorigenic growth in vitro.
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