Identification of novel pathways and molecules able to down-regulate PHOX2B gene expression by in vitro drug screening approaches in neuroblastoma cells

Eleonora Di Zanni, Diego Fornasari, Roberto Ravazzolo, Isabella Ceccherini, Tiziana Bachetti

Research output: Contribution to journalArticle

4 Citations (Scopus)

Abstract

PHOX2B is a transcription factor involved in the regulation of neurogenesis and in the correct differentiation of the autonomic nervous system. The pathogenetic role of PHOX2B in neuroblastoma (NB) is supported by mutations in familial, sporadic and syndromic cases of NB and overexpression of PHOX2B and its target ALK in tumor samples and NB cell lines.Starting from these observations, we have performed in vitro drug screening approaches targeting PHOX2B overexpression as a potential pharmacological means in NB.In particular, in order to identify molecules able to decrease PHOX2B expression, we have evaluated the effects of 70 compounds in IMR-32 cell line stably expressing the luciferase gene under the control of the PHOX2B promoter. Curcumin, SAHA and trichostatin A showed to down-regulate the PHOX2B promoter activity which resulted in a decrease of both protein and mRNA expressions. In addition, we have observed that curcumin acts by interfering with PBX-1/MEIS-1, NF-κB and AP-1 complexes, in this work demonstrated for the first time to regulate the transcription of the PHOX2B gene.Finally, combined drug treatments showed successful effects in down-regulating the expression of both PHOX2B and its target ALK genes, thus supporting the notion of the effectiveness of molecule combination in tumor therapy.

Original languageEnglish
Pages (from-to)43-57
Number of pages15
JournalExperimental Cell Research
Volume336
Issue number1
DOIs
Publication statusPublished - 2015

Fingerprint

Preclinical Drug Evaluations
Neuroblastoma
Down-Regulation
Gene Expression
Curcumin
trichostatin A
Genes
Cell Line
Autonomic Nervous System
Neurogenesis
Transcription Factor AP-1
Luciferases
Neoplasms
Transcription Factors
Pharmacology
Messenger RNA
Mutation
In Vitro Techniques
Pharmaceutical Preparations
Proteins

Keywords

  • Curcumin
  • Drug screening
  • Gene expression regulation
  • Histone deacetylase
  • Neuroblastoma
  • PHOX2B

ASJC Scopus subject areas

  • Cell Biology
  • Medicine(all)

Cite this

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title = "Identification of novel pathways and molecules able to down-regulate PHOX2B gene expression by in vitro drug screening approaches in neuroblastoma cells",
abstract = "PHOX2B is a transcription factor involved in the regulation of neurogenesis and in the correct differentiation of the autonomic nervous system. The pathogenetic role of PHOX2B in neuroblastoma (NB) is supported by mutations in familial, sporadic and syndromic cases of NB and overexpression of PHOX2B and its target ALK in tumor samples and NB cell lines.Starting from these observations, we have performed in vitro drug screening approaches targeting PHOX2B overexpression as a potential pharmacological means in NB.In particular, in order to identify molecules able to decrease PHOX2B expression, we have evaluated the effects of 70 compounds in IMR-32 cell line stably expressing the luciferase gene under the control of the PHOX2B promoter. Curcumin, SAHA and trichostatin A showed to down-regulate the PHOX2B promoter activity which resulted in a decrease of both protein and mRNA expressions. In addition, we have observed that curcumin acts by interfering with PBX-1/MEIS-1, NF-κB and AP-1 complexes, in this work demonstrated for the first time to regulate the transcription of the PHOX2B gene.Finally, combined drug treatments showed successful effects in down-regulating the expression of both PHOX2B and its target ALK genes, thus supporting the notion of the effectiveness of molecule combination in tumor therapy.",
keywords = "Curcumin, Drug screening, Gene expression regulation, Histone deacetylase, Neuroblastoma, PHOX2B",
author = "{Di Zanni}, Eleonora and Diego Fornasari and Roberto Ravazzolo and Isabella Ceccherini and Tiziana Bachetti",
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T1 - Identification of novel pathways and molecules able to down-regulate PHOX2B gene expression by in vitro drug screening approaches in neuroblastoma cells

AU - Di Zanni, Eleonora

AU - Fornasari, Diego

AU - Ravazzolo, Roberto

AU - Ceccherini, Isabella

AU - Bachetti, Tiziana

PY - 2015

Y1 - 2015

N2 - PHOX2B is a transcription factor involved in the regulation of neurogenesis and in the correct differentiation of the autonomic nervous system. The pathogenetic role of PHOX2B in neuroblastoma (NB) is supported by mutations in familial, sporadic and syndromic cases of NB and overexpression of PHOX2B and its target ALK in tumor samples and NB cell lines.Starting from these observations, we have performed in vitro drug screening approaches targeting PHOX2B overexpression as a potential pharmacological means in NB.In particular, in order to identify molecules able to decrease PHOX2B expression, we have evaluated the effects of 70 compounds in IMR-32 cell line stably expressing the luciferase gene under the control of the PHOX2B promoter. Curcumin, SAHA and trichostatin A showed to down-regulate the PHOX2B promoter activity which resulted in a decrease of both protein and mRNA expressions. In addition, we have observed that curcumin acts by interfering with PBX-1/MEIS-1, NF-κB and AP-1 complexes, in this work demonstrated for the first time to regulate the transcription of the PHOX2B gene.Finally, combined drug treatments showed successful effects in down-regulating the expression of both PHOX2B and its target ALK genes, thus supporting the notion of the effectiveness of molecule combination in tumor therapy.

AB - PHOX2B is a transcription factor involved in the regulation of neurogenesis and in the correct differentiation of the autonomic nervous system. The pathogenetic role of PHOX2B in neuroblastoma (NB) is supported by mutations in familial, sporadic and syndromic cases of NB and overexpression of PHOX2B and its target ALK in tumor samples and NB cell lines.Starting from these observations, we have performed in vitro drug screening approaches targeting PHOX2B overexpression as a potential pharmacological means in NB.In particular, in order to identify molecules able to decrease PHOX2B expression, we have evaluated the effects of 70 compounds in IMR-32 cell line stably expressing the luciferase gene under the control of the PHOX2B promoter. Curcumin, SAHA and trichostatin A showed to down-regulate the PHOX2B promoter activity which resulted in a decrease of both protein and mRNA expressions. In addition, we have observed that curcumin acts by interfering with PBX-1/MEIS-1, NF-κB and AP-1 complexes, in this work demonstrated for the first time to regulate the transcription of the PHOX2B gene.Finally, combined drug treatments showed successful effects in down-regulating the expression of both PHOX2B and its target ALK genes, thus supporting the notion of the effectiveness of molecule combination in tumor therapy.

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