Molecular mechanisms of fenretinide-induced apoptosis of neuroblastoma cells
Penny E Lovat1, Marco Corazzari, Bojidar Goranov
1Northern Institute for Cancer Research, University of Newcastle upon Tyne, Newcastle upon Tyne, NE2 4HH, UK.
Abstract:
Synthetic retinoids such as fenretinide [N-(4-hydroxyphenyl)retinamide] induce apoptosis of neuroblastoma cells, act synergistically with chemotherapeutic drugs, and may provide opportunities for novel approaches to neuroblastoma therapy. Fenretinide-induced cell death of neuroblastoma cells is caspase dependent and results in the release of cytochrome c from mitochondria independently of changes in permeability transition. This is mediated by a signaling pathway characterized by the generation of reactive oxygen species (ROS) via 12-lipoxygenase (12-LOX), and an oxidative-stress-dependent induction of the transcription factor, GADD153 and the BCL2-related protein BAK. Upstream events of fenretinide-induced signaling involve increased levels of ceramide as a result of increased sphingomyelinase activity, and the subsequent metabolism of ceramide to gangliosides via glucosylceramide synthase and GD3 synthase. These gangliosides may be involved in the regulation of 12-LOX leading to oxidative stress and apoptosis via the induction of GADD153 and BAK. The targeting of sphingomyelinases or downstream effectors such as 12-LOX or GADD153 may present novel approaches for the development of more effective and selective drugs for neuroblastoma therapy.
Insights
Fenretinide induces neuroblastoma cell death through a caspase-dependent pathway involving reactive oxygen species (ROS) and oxidative stress. Targeting sphingomyelinases or 12-lipoxygenase (12-LOX) may lead to novel neuroblastoma therapies.
Area of Science:
- Biochemistry
- Molecular Biology
- Cancer Research
Background:
- Neuroblastoma is a pediatric cancer with limited therapeutic options.
- Synthetic retinoids like fenretinide show promise in cancer treatment.
- Understanding fenretinide's mechanism is crucial for developing targeted therapies.
Purpose of the Study:
- To elucidate the molecular mechanisms underlying fenretinide-induced apoptosis in neuroblastoma cells.
- To identify key signaling pathways and molecular targets involved in fenretinide's action.
- To explore potential therapeutic strategies based on fenretinide's mechanism.
Main Methods:
- Investigated fenretinide's effects on neuroblastoma cell viability and apoptosis.
- Analyzed caspase activation, cytochrome c release, and mitochondrial function.
- Examined the roles of reactive oxygen species (ROS), 12-lipoxygenase (12-LOX), ceramide metabolism, and GADD153/BAK expression.
Main Results:
- Fenretinide induced caspase-dependent apoptosis, releasing cytochrome c from mitochondria.
- The pathway involved ROS generation via 12-LOX, oxidative stress, and induction of GADD153 and BAK.
- Fenretinide increased ceramide levels, influencing ganglioside metabolism, which may regulate 12-LOX and apoptosis.
Conclusions:
- Fenretinide triggers neuroblastoma cell death through a specific oxidative stress-mediated pathway.
- Targeting sphingomyelinases, 12-LOX, or GADD153 presents potential therapeutic avenues for neuroblastoma.
- Fenretinide's mechanism offers insights for developing more effective and selective neuroblastoma treatments.
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