ERβ-dependent neuroglobin up-regulation impairs 17β-estradiol-induced apoptosis in DLD-1 colon cancer cells upon oxidative stress injury

Marco Fiocchetti, Giulia Camilli, Filippo Acconcia, Stefano Leone, Paolo Ascenzi, Maria Marino

Research output: Contribution to journalArticle

Abstract

Besides other mechanism(s) 17β-estradiol (E2) facilitates neuronal survival by increasing, via estrogen receptor β (ERβ), the levels of neuroglobin (NGB) an anti-apoptotic protein. In contrast, E2 could exert protective effects in cancer cells by activating apoptosis when the ERβ level prevails on that of ERα as in colon cancer cell lines. These apparently contrasting results raise the possibility that E2-induced NGB up-regulation could regulate the ERβ activities shunning this receptor subtype to trigger an apoptotic cascade in neurons but not in non-neuronal cells. Here, human colorectal adenocarcinoma cell line (DLD-1) that only expresses ERβ and HeLa cells transiently transfected with ERβ encoding vector has been used to verify this hypothesis. In addition, neuroblastoma SK-N-BE cells were used as positive control. Surprisingly, E2 also induced NGB up-regulation, in a dose- and time-dependent manner, in DLD-1 cells. The ERβ-mediated activation of p38/MAPK was necessary for this E2 effect. E2 induced NGB re-allocation in mitochondria where, subsequently to an oxidative stress injury (i.e., 100 μM H2O2), NGB interacted with cytochrome c preventing its release into the cytosol and the activation of an apoptotic cascade. As a whole, these results demonstrate that E2-induced NGB up-regulation could act as an oxidative stress sensor, which does not oppose to the pro-apoptotic E2 effect in ERβ-containing colon cancer cells unless a rise of oxidative stress occurs. These results support the concept that oxidative stress plays a critical role in E2-induced carcinogenesis and further open an important scenario to develop novel therapeutic strategies that target NGB against E2-related cancers.

Original languageEnglish
Pages (from-to)128-137
Number of pages10
JournalJournal of Steroid Biochemistry and Molecular Biology
Volume149
DOIs
Publication statusPublished - 2015

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Keywords

  • 17β-Estradiol
  • Apoptosis
  • Colon cancer cell line
  • Estrogen receptor β
  • Neuroglobin
  • Oxidative stress

ASJC Scopus subject areas

  • Biochemistry
  • Clinical Biochemistry
  • Endocrinology
  • Cell Biology
  • Molecular Biology
  • Endocrinology, Diabetes and Metabolism
  • Molecular Medicine
  • Medicine(all)

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