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 language | English |
|---|---|
| Pages (from-to) | 43-57 |
| Number of pages | 15 |
| Journal | Experimental Cell Research |
| Volume | 336 |
| Issue number | 1 |
| DOIs | |
| Publication status | Published - 2015 |
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Keywords
- Curcumin
- Drug screening
- Gene expression regulation
- Histone deacetylase
- Neuroblastoma
- PHOX2B
ASJC Scopus subject areas
- Cell Biology
- Medicine(all)
Cite this
Identification of novel pathways and molecules able to down-regulate PHOX2B gene expression by in vitro drug screening approaches in neuroblastoma cells. / Di Zanni, Eleonora; Fornasari, Diego; Ravazzolo, Roberto; Ceccherini, Isabella; Bachetti, Tiziana.
In: Experimental Cell Research, Vol. 336, No. 1, 2015, p. 43-57.Research output: Contribution to journal › Article
}
TY - JOUR
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.
KW - Curcumin
KW - Drug screening
KW - Gene expression regulation
KW - Histone deacetylase
KW - Neuroblastoma
KW - PHOX2B
UR - http://www.scopus.com/inward/record.url?scp=84943427171&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84943427171&partnerID=8YFLogxK
U2 - 10.1016/j.yexcr.2015.03.025
DO - 10.1016/j.yexcr.2015.03.025
M3 - Article
VL - 336
SP - 43
EP - 57
JO - Experimental Cell Research
JF - Experimental Cell Research
SN - 0014-4827
IS - 1
ER -