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Translatome profiling of neuroblastoma cells CHP134 treated with isotretinoin (13cRA), isorhamnetin (ISR), and their combination

ABSTRACT: Neuroblastoma (NB) is an aggressive childhood tumor, with high-risk cases having a 5-year overall survival probability of about 50%. The multimodal therapeutic scheme of NB includes isotretinoin (13cRA), used in the post-consolidation phase as an anti-proliferative and pro-differentiative agent to minimize residual disease and prevent relapse. Through a small molecule screening, we identified isorhamnetin (ISR) as a synergistic compound with 13cRA in inhibiting up to 80% of NB cell viability. To unveil the molecular mechanisms underlying this synergism, microarray analysis was performed in CHP134 control cells, and cells treated with 13cRA (5uM), ISR (15uM), and their combination. This analysis revealed that 13cRA ISR synergism is accompanied by a marked increase in the expression of the adrenergic receptor α1B (ADRA1B) gene. Administration of doxazosin, a safe α1-antagonist used in pediatric patients, with 13cRA in NB xenografted mice exerted a marked control of tumor growth, while each of the two drugs alone was ineffective. We, therefore, preclinically identify the α1B adrenergic receptor as a novel pharmacological target in NB. We propose evaluating the addition of α1-antagonists in the post-consolidation therapy of NB to more efficiently control residual disease. Keywords: isotretinoin, 13cRA, 13-cis retinoic acid, isorhamnetin, ISR, neuroblastoma, polysome profiling, translatome, adrenergic receptors, α-blockers, combinatorial therapy, synergy

ORGANISM(S): Homo sapiens

PROVIDER: GSE232388 | GEO | 2023/05/29

REPOSITORIES: GEO

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Project description:Neuroblastoma (NB) is the most frequent extracranial solid tumour of childhood. Clinical courses are highly variable, ranging from spontaneous regression/maturation to rapid progression despite intensive multimodal therapy. The estimation of 5-year event free survival in high-risk patients of only about 40 % stresses an importance of novel therapeutic strategies. A number of iron chelators have demonstrated marked in vitro and in vivo anti-tumor activity and are currently being developed as novel anti-cancer agents. Therefore, the potential antitumor effect of iron chelators in NB cancer was investigated. Among the compounds tested, ciclopirox olamine (CPX) was shown to be one of the most effective intracellular iron chelators in NB cells. To unveil the molecular mechanisms underlying the effects of CPX on viability of NB cells, microarray analysis was performed in CHP134 control cells and cells treated with 5 M-BM-5M CPX for 90 minutes. Inclusion of both total RNA (reflecting transcriptional status of the cells) and polysomal RNA (approximating the proteomic representation of the cells) provided us with a deeper understanding of changes in the cells upon CPX treatment. Keywords: ciclopirox olamine, iron chelator, neuroblastoma, translatome profiling, transcriptome profiling. Keywords: ciclopirox olamine, iron chelator, neuroblastoma, translatome profiling, transcriptome profiling, polysomal profiling, polysomal RNA, translational control, translational profiling, polysome profiling Microarray analysis was performed to enable a comprehensive view of the changes in the transcriptional and translational status of the cells in response to the treatment with an iron chelator CPX. Polysomal RNA and total RNA were isolated from vehicle-treated CHP134 cells and CHP134 cells treated with 5 M-BM-5M CPX for 90 minutes. Each condition is represented by three biological replicates, i.e. the experiment was repeated starting each time from cells seeding yielding an independent RNA sample. In total, 12 samples corresponding to 4 conditions were subjected to microarray analysis.

Project description:Neuroblastoma (NB) is the most frequent extracranial solid tumour of childhood. Clinical courses are highly variable, ranging from spontaneous regression/maturation to rapid progression despite intensive multimodal therapy. The estimation of 5-year event free survival in high-risk patients of only about 40 % stresses an importance of novel therapeutic strategies. A number of iron chelators have demonstrated marked in vitro and in vivo anti-tumor activity and are currently being developed as novel anti-cancer agents. Therefore, the potential antitumor effect of iron chelators in NB cancer was investigated. Among the compounds tested, ciclopirox olamine (CPX) was shown to be one of the most effective intracellular iron chelators in NB cells. To unveil the molecular mechanisms underlying the effects of CPX on viability of NB cells, microarray analysis was performed in CHP134 control cells and cells treated with 5 ÂµM CPX for 24 hours. Inclusion of both total RNA (reflecting transcriptional status of the cells) and polysomal RNA (approximating the proteomic representation of the cells) provided us with a deeper understanding of changes in the cells upon CPX treatment. Keywords: ciclopirox olamine, iron chelator, neuroblastoma, translatome profiling, transcriptome profiling, polysomal profiling, polysomal RNA, translational control, translational profiling, polysome profiling Microarray analysis was performed to enable a comprehensive view of the changes in the transcriptional and translational status of the cells in response to the treatment with an iron chelator CPX. Polysomal RNA and total RNA were isolated from vehicle-treated CHP134 cells and CHP134 cells treated with 5 ÂµM CPX for 24 hours. Each condition is represented by three biological replicates, i.e. the experiment was repeated starting each time from cells seeding yielding an independent RNA sample. In total, 12 samples corresponding to 4 conditions were subjected to microarray analysis.

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Translatome profiling of neuroblastoma cells CHP134 treated with isotretinoin (13cRA), isorhamnetin (ISR), and their combination

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