Recently, BDNF was identified as a potential proangiogenic factor for the promotion of endothelial cell survival, induction of neoangiogenesis in ischemic tissues, and increase of VEGF expression in neuroblastoma.
Although expression of the high-affinity neurotrophin receptors, TrkA and TrkB, is of major importance in neuroblastoma, the significance of the expression of the low-affinity neurotrophin receptor, p75, is unclear.
Alternative splicing of the neurotrophin receptor tyrosine kinase TrkA may have a pivotal function in regulating NB behaviour, with reports suggesting that tumour-suppressing signals from TrkA may be converted to oncogenic signals by stress-regulated alternative TrkAIII splicing.
TrkB and its ligand brain-derived neurotrophic factor (BDNF) are preferentially expressed in NB with poor prognosis, conferring invasive and metastatic potential to the tumor cells as well as enhancing therapy resistance.
In the childhood tumor neuroblastoma, high expression of the TrkA neurotrophin receptor is associated with a favorable prognosis and a lack of structural chromosomal changes, whereas TrkB is expressed in aggressive neuroblastomas demonstrating high genomic instability.
In this study, we administered both fibrillar and oligomeric conformations of Abeta(1-42) to differentiated SH-SY5Y, a human neuroblastoma cell line, and measured both phosphorylated cAMP response element-binding protein (CREB), a regulator of BDNF transcription, and BDNF total mRNA.
Both MAPK and PI3K pathways were involved in BDNF protection of NB cells from paclitaxel-induced cell death, while PI3K predominantly mediated BDNF protection of NB cells from etoposide or cisplatin-induced cell death.
Transfection of neuroblastoma SK-N-AS cells or primary rat hippocampal neurons with the small double-stranded interfering RNA (siRNA) targeting BDNF mRNA, but not the scrambled siRNA, resulted in reductions in levels of BDNF mRNA and proteins by more than 70% in the transfected cells as compared with the control group, suggesting an RNAi-mediated, sequence-specific gene silencing.
Since BDNF is one of target genes of cAMP response element-binding protein (CREB), this study examined effects of cocaine on CREB activities in a human neuroblastoma (SK-N-AS) cell line.
These data indicate that BDNF plays a role in regulating VEGF levels in neuroblastoma cells and that targeted therapies to BDNF/TrkB, PI3K, mTOR signal transduction pathways, and/or HIF-1alpha have the potential to inhibit VEGF expression and limit neuroblastoma tumor growth.
These results indicate that Akt is a key signaling component by which BDNF activation of the TrkB signal transduction pathway protects neuroblastoma cells from chemotherapy-induced cell death.
Expression of neurotrophin receptors of the tyrosine kinase receptor (Trk) family is an important prognostic factor in solid tumors including neuroblastoma.
By using a neuroblastoma cell line devoid of neurotrophin receptors and engineered to express either a full-length or a death domain (DD)-truncated form of p75NTR, we demonstrated that Abeta peptide activates the mitogen-activated protein kinases (MAPKs) p38 and c-Jun N-terminal kinase (JNK).
However, the spontaneous regression of neuroblastoma mimics the programmed cell death normally occurring in developing sympathetic cells expressing both TrkA tyrosine kinase A and p75NTR neurotrophin receptor.
We analysed neurotrophin receptor (NTR) expression of neuroblastoma cells by surface biotinylation assays and applied recombinant nerve growth factor (NGF), brain-derived neurotrophic factor, neurotrophin-3 and neurotrophin-4/5 to these cell lines assessing their survival and proliferation in long-term assays lasting 6 days.
In the present study, we examined the regulation of FOXO3a by brain-derived neurotrophic factor (BDNF) in retinoic acid (RA)-differentiated human SH-SY5Y neuroblastoma cells.
This shows that MYCN overexpression per se is not sufficient to induce trkB expression. trkB expression and BDNF responsiveness in neuroblastoma cells can be induced by all-trans-retinoic acid (RA).