Neurotrophin and Neurotrophin Receptor Involvement in Human Neuroblastoma

Ruggeri, Pierdomenico; Farina, Antonietta R.; Cappabianca, Lucia; Ragone, Marzia; Merolle, Stefania; Gulino, Alberto; Mackay, Andrew R.

doi:10.5772/55536

Cited by 7 publications

(19 citation statements)

References 367 publications

(512 reference statements)

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“…As a consequence, TrkAIII is not expressed at the cell surface but accumulates within pre-Golgi membranes and at the centrosome, where it exhibits spontaneous ligand-independent activation. Spontaneous intracellular TrkAIII activation leads to chronic signaling through the IP3K/Akt but not RAS/MAPK pathway and promotes a more stem cell-like, anaplastic, pro-angiogenic, stress-resistant, genetically unstable, tumourigenic and metastatic phenotype [ 1 – 3 , 6 , 7 , 11 – 13 ]. In NB cell lines, alternative TrkAIII splicing is promoted by a hypoxia mimic, suggesting that it represents a mechanism through which tumour suppressing signals from fully spliced TrkA receptors can switch to tumor promoting signals from TrkAIII within the hypoxic tumour microenvironment [ 1 , 2 , 6 ].…”

Section: Introductionmentioning

confidence: 99%

“…Spontaneous intracellular TrkAIII activation leads to chronic signaling through the IP3K/Akt but not RAS/MAPK pathway and promotes a more stem cell-like, anaplastic, pro-angiogenic, stress-resistant, genetically unstable, tumourigenic and metastatic phenotype [ 1 – 3 , 6 , 7 , 11 – 13 ]. In NB cell lines, alternative TrkAIII splicing is promoted by a hypoxia mimic, suggesting that it represents a mechanism through which tumour suppressing signals from fully spliced TrkA receptors can switch to tumor promoting signals from TrkAIII within the hypoxic tumour microenvironment [ 1 , 2 , 6 ]. Furthermore, spontaneous activation of TrkAIII within the ERGIC-COP1 compartment and at the centrosome provides novel alternatives to “classical” cell surface oncogenic receptor tyrosine kinase (RTK) signaling and fuels the growing hypothesis that the RTK oncoprotein mislocalization underpins oncogenic activity [ 11 , 14 , 15 ].…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2017

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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 PDHK1 tyrosine phosphorylation, leading to glycolytic metabolic adaptation. This novel mitochondrial role for TrkAIII provides a potential self-perpetuating, drug reversible way through which tumour microenvironmental stress may maintain the metastasis promoting “Warburg effect” in TrkAIII expressing NBs.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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

et al. 2017

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“…NC cell EMT involves the loss of apical/basal polarity, altered expression of type 1 (E-cadherin and N-cadherin) and type 2 cadherins (cadherins 6, 7 and 8)[ 16 - 19 ], cytoskeletal reorganisation and proteolytic activity. It is initiated by Snai2, FoxD3, Sox9, Sox10 and Twist transcription factors, regulated by BMP, Wnt-planar cell polarity, Frizzled, RhoA-ROCK signalling in coordination with surrounding tissue morphogenesis[ 4 , 6 , 16 ], and involves: connexin-43[ 20 ], clatherin-mediated endocytosis[ 21 ]; cadherin 6B proteolysis[ 21 - 23 ] ; hypoxia-inducible factor (HIF)-a[ 24 - 26 ] ADAMs, γ-secretase and matrix metalloproteinases (MMPs) and matrix components, including collagen, fibronectin, laminin, tenascin, collagen IX, chondroitin-6-sulphate, aggrecan and versecan, which combine to lower intracellular adhesivity and increased motility[ 27 - 30 ]. With respect to the formation of NBs that originate from trunk NC cells, trunk NC cells that delaminate and migrate ventro-laterally via contact inhibited locomotion, co-attraction and chemotaxis, accumulate at the dorsal aorta, mix and then form bi-lateral sympathetic ganglia that go on to innervate various organs and skin[ 6 , 28 - 31 ].…”

Section: The Neural Crestmentioning

confidence: 99%

Mechanisms involved in selecting and maintaining neuroblastoma cancer stem cell populations, and perspectives for therapeutic targeting

Farina¹,

Cappabianca²,

Zelli³

et al. 2021

WJSC

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Pediatric neuroblastomas (NBs) are heterogeneous, aggressive, therapy-resistant embryonal tumours that originate from cells of neural crest (NC) origin and in particular neuroblasts committed to the sympathoadrenal progenitor cell lineage. Therapeutic resistance, post-therapeutic relapse and subsequent metastatic NB progression are driven primarily by cancer stem cell (CSC)-like subpopulations, which through their self-renewing capacity, intermittent and slow cell cycles, drug-resistant and reversibly adaptive plastic phenotypes, represent the most important obstacle to improving therapeutic outcomes in unfavourable NBs. In this review, dedicated to NB CSCs and the prospects for their therapeutic eradication, we initiate with brief descriptions of the unique transient vertebrate embryonic NC structure and salient molecular protagonists involved NC induction, specification, epithelial to mesenchymal transition and migratory behaviour, in order to familiarise the reader with the embryonic cellular and molecular origins and background to NB. We follow this by introducing NB and the potential NC-derived stem/progenitor cell origins of NBs, before providing a comprehensive review of the salient molecules, signalling pathways, mechanisms, tumour microenvironmental and therapeutic conditions involved in promoting, selecting and maintaining NB CSC subpopulations, and that underpin their therapy-resistant, self-renewing metastatic behaviour. Finally, we review potential therapeutic strategies and future prospects for targeting and eradication of these bastions of NB therapeutic resistance, post-therapeutic relapse and metastatic progression.

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“…Neuroblastomas (NB) are aggressive embryonic tumours of neural crest origin, derived from immature sympathetic neuroblasts [24]. These primitive tumours initiate under conditions that impair sympathetic neuroblast culling during development, reported to depend upon either loss of the KIF1B gene associated with chromosome 1p36-deletion, germline KIF1B mutations or Nmyc amplification [25–33].…”

Section: Introductionmentioning

confidence: 99%

Discovery, characterization and potential roles of a novel NF-YAx splice variant in human neuroblastoma

Cappabianca

Farina

Infante

et al. 2019

J Exp Clin Cancer Res

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BackgroundIdentification of novel cancer-associated splice variants is of potential diagnostic, prognostic and therapeutic importance. NF-Y transcription factor is comprised of NF-YA, NF-YB and NF-YC subunits, binds inverted CCAAT-boxes in ≈70% of gene promoters, regulates > 1000 cancer-associated genes and proteins involved in proliferation, staminality, differentiation, apoptosis, metabolism and is subject to component alternative splicing. RT-PCR evaluation of alternative NF-YA splicing in primary human neuroblastomas (NBs), led to discovery of a novel NF-YAx splice variant, also expressed during mouse embryo development and induced by doxorubicin in NB cells. Here, we report the discovery and characterisation of NF-YAx and discus its potential roles in NB.MethodsNF-YAx cDNA was RT-PCR-cloned from a stage 3 NB (provided by the Italian Association of Haematology and Paediatric Oncology, Genova, IT), sequenced and expressed as a protein using standard methods and compared to known fully-spliced NF-YAl and exon B-skipped NF-YAs isoforms in: EMSAs for capacity to form NF-Y complexes; by co-transfection, co-immunoprecipitation and Western blotting for capacity to bind Sp1; by IF for localisation; in AO/EtBr cell-death and colony formation assays for relative cytotoxicity, and by siRNA knockdown, use of inhibitors and Western blotting for potential mechanisms of action. Stable SH-SY5Y transfectants of all three NF-YA isoforms were also propagated and compared by RT-PCR and Western blotting for differences in cell-death and stem cell (SC)-associated gene expression, in cell-death assays for sensitivity to doxorubicin and in in vitro proliferation, substrate-independent growth and in vivo tumour xenograft assays for differences in growth and tumourigenic capacity.ResultsNF-YAx was characterized as a novel variant with NF-YA exons B, D and partial F skipping, detected in 20% of NF-YA positive NBs, was the exclusive isoform in a stage 3 NB, expressed in mouse stage E11.5–14 embryos and induced by doxorubicin in SH-SY5Y NB cells. The NF-YAx protein exhibited nuclear localisation, competed with other isoforms in CCAAT box-binding NF-Y complexes but, in contrast to other isoforms, did not bind Sp1. NF-YAx expression in neural-related progenitor and NB cells repressed Bmi1 expression, induced KIF1Bβ expression and promoted KIF1Bβ-dependent necroptosis but in NB cells also selected tumourigenic, doxorubicin-resistant, CSC-like sub-populations, resistant to NF-YAx cytotoxicity.ConclusionsThe discovery of NF-YAx in NBs, its expression in mouse embryos and induction by doxorubicin in NB cells, unveils a novel NF-YA splice mechanism and variant, regulated by and involved in development, genotoxic-stress and NB. NF-YAx substitution of other isoforms in NF-Y complexes and loss of capacity to bind Sp1, characterises this novel isoform as a functional modifier of NF-Y and its promotion of KIF1Bβ-dependent neural-lineage progenitor and NB cell necroptosis, association with doxorubicin-induced necroptosis and expression in mouse embryo...

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Neurotrophin and Neurotrophin Receptor Involvement in Human Neuroblastoma

Cited by 7 publications

References 367 publications

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

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

Mechanisms involved in selecting and maintaining neuroblastoma cancer stem cell populations, and perspectives for therapeutic targeting

Discovery, characterization and potential roles of a novel NF-YAx splice variant in human neuroblastoma

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