A drug that induces the microRNA miR-124 enables differentiation of retinoic acid–resistant neuroblastoma cells DOI
Lien D. Nguyen,

Satyaki Sengupta,

Kevin I. Cho

et al.

Science Signaling, Journal Year: 2025, Volume and Issue: 18(882)

Published: April 15, 2025

Tumor cell heterogeneity in neuroblastoma, a pediatric cancer arising from neural crest–derived progenitor cells, presents clinical challenges. Unlike adrenergic (ADRN) neuroblastoma cells with mesenchymal (MES) identity are resistant to chemotherapy and retinoid therapy, which contributes relapses treatment failures. We explored whether up-regulation of the neurogenic, tumor suppressor microRNA miR-124 could promote differentiation retinoic acid–resistant MES cells. Leveraging our screen for miRNA-modulatory small molecules, we identified validated tyrosine phosphoinositide kinase inhibitor PP121 as robust inducer miR-124. Combining BDNF-activating bufalin synergistically arrested proliferation promoted sustained MES/heterogeneous SK-N-AS over several weeks. This protocol also resulted multiple glioblastoma lines. RNA-seq analysis differentiated revealed replacement ADRN core regulatory circuitry circuitries associated chromaffin Schwann precursors. Furthermore, was inhibition CDK4/CDK6 pathway activation transcriptional program that correlated improved outcomes patients neuroblastoma. Our findings suggest an approach translational potential induce therapy-resistant cancers nervous system. Moreover, these long-lived, be used study mechanisms underlying biology therapies.

Language: Английский

c-Jun promotes neuroblastoma cell differentiation by inhibiting APC formation via CDC16 and reduces neuroblastoma malignancy DOI Creative Commons
Yunyun Wang, Jingjing Huang, Zhenhua Song

et al.

Biology Direct, Journal Year: 2025, Volume and Issue: 20(1)

Published: March 27, 2025

Abstract Neuroblastoma is a pediatric embryonal malignancy characterized by impaired neuronal differentiation. Differentiation status in neuroblastoma strongly affects the clinical outcome, thus, enforcement of differentiation becomes treatment strategy for this disease. However, molecular mechanisms that control are poorly understood. As an extensively studied protein activator protein-1 (AP-1) complex, c-Jun involved numerous cell regulations such as proliferation, survival and In current study, we demonstrated expression was upregulated retinoic acid (RA) flow cytometry assay indicated overexpression arrested cycle to G1 phase, which, turn, promoted initiation Co-immunoprecipitation (co-IP) showed competitively interacted with CDC16, key subunit anaphase-promoting complex (APC), resulting reduced APC formation inhibition progression. Furthermore, EdU proliferation transwell experiment inhibited migration via interacting sequestering CDC16. These findings identify regulator may represent promising therapeutic target induce interaction between

Language: Английский

Citations

0
A drug that induces the microRNA miR-124 enables differentiation of retinoic acid–resistant neuroblastoma cells DOI
Lien D. Nguyen,

Satyaki Sengupta,

Kevin I. Cho

et al.

Science Signaling, Journal Year: 2025, Volume and Issue: 18(882)

Published: April 15, 2025

Tumor cell heterogeneity in neuroblastoma, a pediatric cancer arising from neural crest–derived progenitor cells, presents clinical challenges. Unlike adrenergic (ADRN) neuroblastoma cells with mesenchymal (MES) identity are resistant to chemotherapy and retinoid therapy, which contributes relapses treatment failures. We explored whether up-regulation of the neurogenic, tumor suppressor microRNA miR-124 could promote differentiation retinoic acid–resistant MES cells. Leveraging our screen for miRNA-modulatory small molecules, we identified validated tyrosine phosphoinositide kinase inhibitor PP121 as robust inducer miR-124. Combining BDNF-activating bufalin synergistically arrested proliferation promoted sustained MES/heterogeneous SK-N-AS over several weeks. This protocol also resulted multiple glioblastoma lines. RNA-seq analysis differentiated revealed replacement ADRN core regulatory circuitry circuitries associated chromaffin Schwann precursors. Furthermore, was inhibition CDK4/CDK6 pathway activation transcriptional program that correlated improved outcomes patients neuroblastoma. Our findings suggest an approach translational potential induce therapy-resistant cancers nervous system. Moreover, these long-lived, be used study mechanisms underlying biology therapies.

Language: Английский

Citations

0