Targeting of PHOX2B expression allows the identification of drugs effective in counteracting neuroblastoma cell growth
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Eleonora Di Zanni1,2, Giovanna Bianchi3, Roberto Ravazzolo1,4
1U.O.C. Genetica Medica, Istituto Giannina Gaslini, Genova, Italy.
Abstract:
The pathogenic role of the PHOX2B gene in neuroblastoma is indicated by heterozygous mutations in neuroblastoma patients and by gene overexpression in both neuroblastoma cell lines and tumor samples. PHOX2B encodes a transcription factor which is crucial for the correct development and differentiation of sympathetic neurons. PHOX2B overexpression is considered a prognostic marker for neuroblastoma and it is also used by clinicians to monitor minimal residual disease. Furthermore, it has been observed that neuronal differentiation in neuroblastoma is dependent on down-regulation of PHOX2B expression, which confirms that PHOX2B expression may be considered a target in neuroblastoma. Here, PHOX2B promoter or 3' untranslated region were used as molecular targets in an in vitro high-throughput approach that led to the identification of molecules able to decrease PHOX2B expression at transcriptional and likely even at post-transcriptional levels. Further functional investigations carried out on PHOX2B mRNA levels and biological consequences, such as neuroblastoma cell apoptosis and growth, showed that chloroquine and mycophenolate mofetil are most promising agents for neuroblastoma therapy based on down-regulation of PHOX2B expression. Finally, a strong correlation between the effect of drugs in terms of down-regulation of PHOX2B expression and of biological consequences in neuroblastoma cells confirms the role of PHOX2B as a potential molecular target in neuroblastoma.
Insights
PHOX2B gene overexpression drives neuroblastoma. Researchers identified molecules targeting PHOX2B, finding chloroquine and mycophenolate mofetil effective in reducing tumor cell growth and promoting apoptosis.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- The PHOX2B gene plays a critical role in sympathetic neuron development and differentiation.
- PHOX2B mutations and overexpression are implicated in neuroblastoma pathogenesis.
- PHOX2B overexpression serves as a prognostic marker and for monitoring minimal residual disease in neuroblastoma.
Purpose of the Study:
- To investigate PHOX2B as a therapeutic target in neuroblastoma.
- To identify molecules capable of down-regulating PHOX2B expression.
- To evaluate the therapeutic potential of identified agents in neuroblastoma models.
Main Methods:
- Utilized an in vitro high-throughput screening approach targeting the PHOX2B promoter and 3' untranslated region.
- Assessed the impact of identified molecules on PHOX2B mRNA levels and neuroblastoma cell apoptosis and growth.
- Correlated drug-induced PHOX2B down-regulation with observed biological effects.
Main Results:
- Identified molecules that decrease PHOX2B expression at transcriptional and post-transcriptional levels.
- Chloroquine and mycophenolate mofetil demonstrated significant efficacy in reducing neuroblastoma cell proliferation and inducing apoptosis.
- A strong correlation was observed between PHOX2B down-regulation and therapeutic effects.
Conclusions:
- PHOX2B is a validated molecular target for neuroblastoma therapy.
- Chloroquine and mycophenolate mofetil show promise as novel therapeutic agents for neuroblastoma by targeting PHOX2B.
- Down-regulation of PHOX2B expression is a viable strategy for neuroblastoma treatment.
