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Sorafenib-induced mitochondrial complex I inactivation and cell death in human neuroblastoma cells
Vibeke Hervik Bull1, Krishnaraj Rajalingam, Bernd Thiede
1The Biotechnology Centre of Oslo, University of Oslo , P.O. Box 1125 Blindern, 0317 Oslo, Norway.
Abstract:
Sorafenib is a multikinase inhibitor that is approved for use against renal cell and hepatocellular carcinoma. We found that sorafenib potently induced cell death in human neuroblastoma cells. To understand the molecular basis of sorafenib-mediated cell death in human SH-SY5Y cells, we performed a temporal quantitative proteome analysis. The results showed significant quantitative changes of 193 unique proteins. Bioinformatics-assisted pathway analysis of the regulated proteins revealed that mitochondrial proteins, especially components of the electron transport chain and the mitochondrial ribosomes, were significantly affected upon exposure to sorafenib. The observed down-regulation of the respiratory chain complex I (NADH dehydrogenase) was accompanied with loss of mitochondrial transmembrane potential (Δψm) and complete impairment of complex I enzyme activity. The destabilization of complex I subunits was consistent, rapid, and independent of caspase activation as well as Bcl-2 overexpression. This study provides an overview of the molecular machinery driving sorafenib-mediated cell death in neuroblastoma cells and suggests that sorafenib could be a potential therapeutic drug for the treatment of neuroblastoma.
Insights
Sorafenib induces potent cell death in neuroblastoma cells by impacting mitochondrial function. This study reveals molecular mechanisms, suggesting sorafenib as a potential neuroblastoma treatment.
Area of Science:
- Oncology
- Molecular Biology
- Biochemistry
Background:
- Sorafenib is an approved multikinase inhibitor for renal cell and hepatocellular carcinoma.
- Neuroblastoma is a pediatric cancer with limited treatment options.
Purpose of the Study:
- To elucidate the molecular mechanisms of sorafenib-induced cell death in human neuroblastoma cells.
- To investigate the proteomic changes associated with sorafenib treatment in SH-SY5Y neuroblastoma cells.
Main Methods:
- Temporal quantitative proteome analysis of SH-SY5Y cells treated with sorafenib.
- Bioinformatics-assisted pathway analysis to identify affected cellular processes.
- Assessment of mitochondrial function, including transmembrane potential and Complex I activity.
Main Results:
- Sorafenib induced significant cell death in human neuroblastoma cells.
- Proteomic analysis identified 193 differentially regulated proteins, with a notable impact on mitochondrial components.
- Down-regulation of respiratory chain Complex I (NADH dehydrogenase) led to impaired mitochondrial function and loss of transmembrane potential.
- Complex I destabilization was rapid and independent of caspase activation or Bcl-2 overexpression.
Conclusions:
- Sorafenib effectively induces cell death in neuroblastoma cells through disruption of mitochondrial respiratory chain Complex I.
- The findings highlight the potential of sorafenib as a therapeutic agent for neuroblastoma treatment.
- This study provides a molecular framework for understanding sorafenib's action in neuroblastoma.
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