Research Papers:

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

Luciana Gneo, Pierdomenico Ruggeri, Lucia Cappabianca, Antonietta Rosella Farina, Natalia Di Ianni and Andrew Reay Mackay _

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Oncotarget. 2016; 7:80820-80841. https://doi.org/10.18632/oncotarget.13098

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Luciana Gneo1,*, Pierdomenico Ruggeri1,*, Lucia Cappabianca1, Antonietta Rosella Farina1, Natalia Di Ianni1, Andrew Reay Mackay1

1Department of Applied Clinical and Biotechnological Sciences, University of L'Aquila, L’Aquila 67100, Italy

*These authors contributed equally to this work

Correspondence to:

Andrew Reay Mackay, email: [email protected]

Keywords: TrkAIII oncoprotein, TRAIL, apoptosis, neuroblastoma, SH-SY5Y

Received: October 07, 2016     Accepted: October 28, 2016     Published: November 04, 2016


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.

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