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Inhibition of the Mevalonate Pathway Targets Neuroblastoma Stem Cells
Michelle V Green1,2, Jessie L Reed3, Cameron D Zielinski1,2
1Department of Molecular and Precision Medicine, Penn State College of Medicine, Hershey, Pennsylvania, USA.
Introduction:
High-risk neuroblastoma is a difficult-to-treat cancer with high rates of recurrence and treatment resistance, likely driven by a population of cancer stem cells. Multiple previous studies have suggested that the use of mevalonate pathway inhibitors, such as statins and bisphosphonates, may have anticancer activity against high-risk tumors.
Methods:
We aimed to observe the use of mevalonate pathway inhibitors against the cancer stem cell population of high-risk neuroblastoma cell lines SH-SY5Y, SK-N-AS, and SK-N-BE(2)-C using spheroid-based assays.
Results:
We observed significant reductions in spheroid formation capability, stem cell frequency, and stemness properties of these neuroblastoma cancer stem cells with fluvastatin and zoledronate treatment.
Conclusion:
Treatment with mevalonate pathway inhibitors leads to reduced neuroblastoma cancer stem cell function through reductions in protein geranylgeranylation.
Insights
Mevalonate pathway inhibitors like statins and bisphosphonates reduce neuroblastoma cancer stem cell function. This targeted approach inhibits spheroid formation and stemness properties, offering new therapeutic avenues.
Area of Science:
- Oncology
- Cancer Stem Cell Biology
- Pharmacology
Background:
- High-risk neuroblastoma is a challenging cancer with frequent recurrence and treatment resistance.
- Cancer stem cells are implicated as a key driver of neuroblastoma's aggressive nature.
- Mevalonate pathway inhibitors, including statins and bisphosphonates, have shown potential anticancer effects.
Purpose of the Study:
- To investigate the efficacy of mevalonate pathway inhibitors against high-risk neuroblastoma cancer stem cells.
- To assess the impact of these inhibitors on neuroblastoma spheroid formation and stemness characteristics.
Main Methods:
- Utilized spheroid-based assays with high-risk neuroblastoma cell lines (SH-SY5Y, SK-N-AS, SK-N-BE(2)-C).
- Treated cells with specific mevalonate pathway inhibitors: fluvastatin and zoledronate.
Main Results:
- Observed significant reductions in spheroid formation capability.
- Demonstrated decreased stem cell frequency and stemness properties in treated neuroblastoma cells.
- Fluzolmedronate and zoledronate treatments were effective against cancer stem cell populations.
Conclusions:
- Mevalonate pathway inhibitors effectively reduce neuroblastoma cancer stem cell function.
- The observed effects are linked to reductions in protein geranylgeranylation.
- These findings suggest a potential therapeutic strategy targeting cancer stem cells in neuroblastoma.
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