TrkAIII signals endoplasmic reticulum stress to the mitochondria in neuroblastoma cells, resulting in glycolytic metabolic adaptation

Oncotarget
Antonietta R FarinaAndrew R Mackay

Abstract

Alternative TrkAIII splicing characterises advanced stage metastatic disease and post-therapeutic relapse in neuroblastoma (NB), and in NB models TrkAIII exhibits oncogenic activity. In this study, we report a novel role for TrkAIII in signaling ER stress to the mitochondria in SH-SY5Y NB cells that results in glycolytic metabolic adaptation. The ER stress-inducing agents DTT, A23187 and thapsigargin activated the ER stress-response in control pcDNA SH-SY5Y and TrkAIII expressing SH-SY5Y cells and in TrkAIII SH-SY5Y cells increased TrkAIII targeting to mitochondria and internalisation into inner-mitochondrial membranes. Within inner-mitochondrial membranes, TrkAIII was subjected to Omi/HtrA2-dependent cleavage to tyrosine phosphorylated 45-48kDa carboxyl terminal active fragments, localised predominantly in tyrosine kinase-domain mitochondrial matrix orientation. This stress-induced activation of mitochondrial TrkAIII was associated with increased ROS production, prevented by the ROS scavenger Resveratrol and underpinned by changes in Ca2+ movement, implicating ROS/Ca2+ interplay in overcoming the mitochondrial TrkAIII activation threshold. Stress-induced, cleavage-activation of mitochondrial TrkAIII resulted in mitochondrial P...Continue Reading

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Citations

Jun 20, 2018·Journal of Experimental & Clinical Cancer Research : CR·Antonietta Rosella FarinaAndrew Reay Mackay
Jun 17, 2020·Journal of Experimental & Clinical Cancer Research : CR·Antonietta Rosella FarinaAndrew Reay Mackay
Oct 24, 2019·Journal of Experimental & Clinical Cancer Research : CR·Lucia CappabiancaAndrew Reay Mackay

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Datasets Mentioned

BETA
GM130

Methods Mentioned

BETA
PCR
transfection
electrophoresis
FCS
fluorescence microscopy

Software Mentioned

Leica M500 Image Manager
Image J Fiji

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