p75 neurotrophin receptor and fenretinide-induced signaling in neuroblastoma.

Abstract

PURPOSE:

Neuroblastoma is the most common extracranial solid tumor of childhood. The retinoic acid analogue, fenretinide (4-hydroxyphenyl retinamide; 4-HPR), induces apoptosis in neuroblastoma cells in vitro and is currently in clinical trials for children with refractory neuroblastoma. We have previously shown that expression of the p75 neurotrophin receptor (p75NTR) enhances apoptosis induction and mitochondrial accumulation of reactive oxygen species by 4-HPR in neuroblastoma cells. We now examine the signaling events that underlie this effect.

METHODS:

Systematic examination of pro- and anti-apoptotic signaling effectors was performed by Western blot. Specific inhibitors of JNK phosphorylation and scavengers of mitochondrial reactive oxygen species were used to demonstrate the roles of these phenomena in the enhancement of fenretinide efficacy.

RESULTS:

The present studies demonstrate that enhancement of 4-HPR-induced apoptosis by p75NTR is dependent upon p38MAPK phosphorylation, JNK phosphorylation, caspase 3 activation, Akt cleavage, and decreased Akt phosphorylation. In addition, treatment with 4-HPR results in upregulation of MKK4 and MEKK1, and phosphorylation of MKK3/6. Efforts to enhance the efficacy of 4-HPR and to identify those tumors most likely to respond to it might exploit these effectors of 4-HPR-induced apoptosis.

CONCLUSIONS:

Pharmacological agents that enhance MKK4 or MEKK1 expression or JNK expression or phosphorylation may enhance efficacy of 4-HPR in neuroblastomas that do not express high levels of p75NTR.

• Authors: Veena R Ganeshan, Nina F Schor
• Journal: Cancer chemotherapy and pharmacology (Cancer Chemother Pharmacol) Vol. 73 Issue 2 Pg. 271-9 (Feb 2014) ISSN: 1432-0843 [Electronic] Germany
• PMID: 24253178 (Publication Type: Journal Article)

Chemical References

• Antineoplastic Agents
• NGFR protein, human
• Nerve Tissue Proteins
• Reactive Oxygen Species
• Receptors, Nerve Growth Factor
• Fenretinide
• Oncogene Protein v-akt
• p38 Mitogen-Activated Protein Kinases
• MAP Kinase Kinase 4

Topics

• Antineoplastic Agents (pharmacology)
• Apoptosis (drug effects)
• Cell Line, Tumor
• Down-Regulation (drug effects)
• Fenretinide (pharmacology)
• Gene Knockdown Techniques
• Humans
• MAP Kinase Kinase 4 (metabolism)
• Mitochondria (drug effects, metabolism)
• Nerve Tissue Proteins (deficiency, genetics, metabolism)
• Neuroblastoma (drug therapy, metabolism, pathology)
• Oncogene Protein v-akt (metabolism)
• Phosphorylation (drug effects)
• Reactive Oxygen Species (metabolism)
• Receptors, Nerve Growth Factor (deficiency, genetics, metabolism)
• Signal Transduction (drug effects)
• Transfection
• p38 Mitogen-Activated Protein Kinases (metabolism)