The Role of p75NTR and Its Signaling Pathways in Fenretinide-Induced Apoptosis in Neuroblastoma Cell
Neuroblastoma, one of the most common extracranial tumors in children is derived from neural crest progenitor cells. Clinical observations of spontaneous regression of neuroblastomas by differentiation to a benign phenotype and apoptosis have generated interest in drugs that can mimic these processes. p75NTR is a neurotrophin receptor involved in late developmental and postnatal apoptosis suggesting that it is directly involved in neuroblastoma development. p75NTR has pro-apoptotic as well as anti-apoptotic properties depending on the cell type, intracellular conditions and relative amounts in the cell. 4-hydroxyphenyl retinamide (4HPR) is a synthetic analog of retinoic acid which induces apoptosis in neuroblastoma cells and is currently being administered in Phase III clinical trials in neuroblastoma therapy.
The overall goal is to understand the role of p75NTR and its signaling pathways in Fenretinide (4-hydroxyphenyl retinamide - 4HPR) induced apoptosis in neuroblastoma cells and determine if JNK phosphorylation is a mediator of this effect.
Our initial results show reduced viability in response to 4HPR treatment in a variety of neuroblastoma cell lines such as SH-EP1 and SK-N-SH cells which is inhibited with p75NTR knockdown. Treatment of SH-EP1 cells with 4HPR for 72 hours causes a significant increase in mitochondrial superoxide production. The pro-apoptotic effect of 4HPR is inhibited when pretreated with dehydro-ascorbic acid (mitochondrial antioxidant) or complex II inhibitors.
This will facilitate the development of combination chemotherapeutics for the treatment of residual disease and prevent disease recurrence by creating conditions of increased oxidative stress and enhance response of tumors to 4HPR treatment.