Induction of GADD153 and Bak: Novel molecular targets of fenretinide-induced apoptosis of neuroblastoma

Penny E. Lovat, Serafina Oliverio, Marco Corazzari, Marco Ranalli, Andy D J Pearson, Gerry Melino, Mauro Piacentini, Christopher P F Redfern

Research output: Contribution to journalArticle

Abstract

Unlike 13-cis retinoic acid, the synthetic retinoid fenretinide induces apoptosis of neuroblastoma cells and in vitro acts synergistically with the chemotherapeutic drugs, cisplatin, etoposide and carboplatin. The stress-induced transcription factor GADD153 and the Bcl2-related protein Bak are upregulated in response to fenretinide. Although fenretinide is a partial retinoic acid receptor (RAR)-β/γ agonist, RARβ/γ antagonists do not block the induction of GADD153 or Bak by fenretinide. Conversely, the induction of GADD153 and Bak is blocked by antioxidants. Neither GADD153 or Bak were induced by chemotherapeutic agents but over expression of GADD153 results in increased sensitivity to fenretinide-induced apoptosis. Therefore, fenretinide induces apoptosis via RAR-dependent and -independent pathways in which the RAR-independent pathway is characterised by the reactive oxygen species-dependent induction of GADD153 and Bak. The targeting of GADD153 and Bak in neuroblastoma cells may be novel pathways for the development of drugs inducing apoptosis of neuroblastoma with improved tumour specificity.

Original languageEnglish
Pages (from-to)157-163
Number of pages7
JournalCancer Letters
Volume197
Issue number1-2
DOIs
Publication statusPublished - Jul 18 2003

Fingerprint

Fenretinide
Neuroblastoma
Retinoic Acid Receptors
Apoptosis
bcl-2 Homologous Antagonist-Killer Protein
Isotretinoin
Carboplatin
Retinoids
Etoposide
Pharmaceutical Preparations
Cisplatin
Reactive Oxygen Species
Transcription Factors
Antioxidants

Keywords

  • Apoptosis
  • Bak
  • Bcl2
  • Carboplatin
  • Chemotherapeutic drugs
  • Cisplatin
  • Differentiation
  • Endoplasmic reticulum stress
  • Etoposide
  • Fenretinide
  • Free radicals
  • GADD153
  • N-(4-hydroxyphenyl)retinamide
  • Neuroblastoma
  • Reactive oxygen
  • Resistance
  • Retinoic acid

ASJC Scopus subject areas

  • Cancer Research
  • Molecular Biology
  • Oncology

Cite this

Lovat, P. E., Oliverio, S., Corazzari, M., Ranalli, M., Pearson, A. D. J., Melino, G., ... Redfern, C. P. F. (2003). Induction of GADD153 and Bak: Novel molecular targets of fenretinide-induced apoptosis of neuroblastoma. Cancer Letters, 197(1-2), 157-163. https://doi.org/10.1016/S0304-3835(03)00098-3

Induction of GADD153 and Bak : Novel molecular targets of fenretinide-induced apoptosis of neuroblastoma. / Lovat, Penny E.; Oliverio, Serafina; Corazzari, Marco; Ranalli, Marco; Pearson, Andy D J; Melino, Gerry; Piacentini, Mauro; Redfern, Christopher P F.

In: Cancer Letters, Vol. 197, No. 1-2, 18.07.2003, p. 157-163.

Research output: Contribution to journalArticle

Lovat, Penny E. ; Oliverio, Serafina ; Corazzari, Marco ; Ranalli, Marco ; Pearson, Andy D J ; Melino, Gerry ; Piacentini, Mauro ; Redfern, Christopher P F. / Induction of GADD153 and Bak : Novel molecular targets of fenretinide-induced apoptosis of neuroblastoma. In: Cancer Letters. 2003 ; Vol. 197, No. 1-2. pp. 157-163.
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AB - Unlike 13-cis retinoic acid, the synthetic retinoid fenretinide induces apoptosis of neuroblastoma cells and in vitro acts synergistically with the chemotherapeutic drugs, cisplatin, etoposide and carboplatin. The stress-induced transcription factor GADD153 and the Bcl2-related protein Bak are upregulated in response to fenretinide. Although fenretinide is a partial retinoic acid receptor (RAR)-β/γ agonist, RARβ/γ antagonists do not block the induction of GADD153 or Bak by fenretinide. Conversely, the induction of GADD153 and Bak is blocked by antioxidants. Neither GADD153 or Bak were induced by chemotherapeutic agents but over expression of GADD153 results in increased sensitivity to fenretinide-induced apoptosis. Therefore, fenretinide induces apoptosis via RAR-dependent and -independent pathways in which the RAR-independent pathway is characterised by the reactive oxygen species-dependent induction of GADD153 and Bak. The targeting of GADD153 and Bak in neuroblastoma cells may be novel pathways for the development of drugs inducing apoptosis of neuroblastoma with improved tumour specificity.

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