TRAIL induces pro-apoptotic crosstalk between the TRAIL-receptor signaling pathway and TrkAIII in SH-SY5Y cells, unveiling a potential therapeutic "Achilles heel" for the TrkAIII oncoprotein in neuroblastoma.
TrkAIII expression in neuroblastoma (NB) associates with advanced stage disease, worse prognosis, post therapeutic relapse, and in NB models TrkAIII exhibits oncogenic activity and promotes chemotherapeutic-resistance. Here, we report a potential therapeutic "Achilles heel" for the TrkAIII oncoprotein in a SH-SY5Y NB model that is characterised by one-way TRAIL-induced, pro-apoptotic crosstalk between the TRAIL receptor signaling pathway and TrkAIII that results in the delayed induction of apoptosis. In TrkAIII SH-SY5Y cells, blocked in the intrinsic apoptosis pathway by elevated constitutive Bcl-2, Bcl-xL and Mcl-1 expression, TRAIL induced delayed caspase-dependent apoptosis via the extrinsic pathway and completely abrogated tumourigenic capacity in vitro. This effect was initiated by TRAIL-induced SHP-dependent c-Src activation, the induction of TrkAIII/SHP-1/c-Src complexing leading to SHP-mediated TrkAIII de-phosphorylation, subsequent induction of complexing between de-phosphorylated TrkAIII and cFLIP associated with a time-dependent increase the caspase-8 to cFLIP ratio at activated death receptors, resulting in delayed caspase cleavage and caspase-dependent apoptosis. We also confirm rate-limiting roles for c-FLIP and Mcl-1 in regulating the sensitivity of TrkAIII SH-SY5Y cells to TRAIL-induced apoptosis via the extrinsic and intrinsic pathways, respectively. Our study unveils a novel mechanism for the TRAIL-induced apoptosis of TrkAIII expressing NB cells that depends upon SHP/Src-mediated crosstalk between the TRAIL-receptor signaling pathway and TrkAIII, and supports a novel potential pro-apoptotic therapeutic use for TRAIL in TrkAIII expressing NB.
Department of Applied Clinical and Biotechnological Sciences, University of L'Aquila, L'Aquila 67100, Italy.
Luciana
L
Gneo
Department of Applied Clinical and Biotechnological Sciences, University of L'Aquila, L'Aquila 67100, Italy.
Pierdomenico
P
Ruggeri
Department of Applied Clinical and Biotechnological Sciences, University of L'Aquila, L'Aquila 67100, Italy.
Lucia
L
Cappabianca
Department of Applied Clinical and Biotechnological Sciences, University of L'Aquila, L'Aquila 67100, Italy.
Antonietta Rosella
AR
Farina
Department of Applied Clinical and Biotechnological Sciences, University of L'Aquila, L'Aquila 67100, Italy.
Natalia
N
Di Ianni
Department of Applied Clinical and Biotechnological Sciences, University of L'Aquila, L'Aquila 67100, Italy.
Andrew Reay
AR
Mackay
D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D051017:Apoptosis Regulatory Proteins / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D004305:Dose-Response Relationship, Drug; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D006801:Humans; D009447:Neuroblastoma / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D010766:Phosphorylation; D054558:Protein Tyrosine Phosphatases, Non-Receptor / Q000235:genetics / Q000378:metabolism; D034622:RNA Interference; D020239:Receptor Cross-Talk; D020917:Receptor, trkA / Q000235:genetics / Q000378:metabolism*; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand / Q000819:agonists* / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000494:pharmacology*; D013997:Time Factors; D014162:Transfection; D019061:src-Family Kinases / Q000235:genetics / Q000378:metabolism
D000970:Antineoplastic Agents; D051017:Apoptosis Regulatory Proteins; C000611485:NTRK1 protein, human; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; D053221:TNF-Related Apoptosis-Inducing Ligand; C505653:TNFSF10 protein, human; D020917:Receptor, trkA; D019061:src-Family Kinases; D054558:Protein Tyrosine Phosphatases, Non-Receptor
SH-SY5Y; TRAIL; TrkAIII oncoprotein; apoptosis; neuroblastoma