Resistance of neuroblastoma GI-ME-N cell line to glutathione depletion involves Nrf2 and heme oxygenase-1

Anna Lisa Furfaro, José Raúl Zumba MacAy, Barbara Marengo, Mariapaola Nitti, Alessia Parodi, Daniela Fenoglio, Umberto Maria Marinari, Maria Adelaide Pronzato, Cinzia Domenicotti, Nicola Traverso

Research output: Contribution to journalArticle

Abstract

Cancer cell survival is known to be related to the ability to counteract oxidative stress, and glutathione (GSH) depletion has been proposed as a mechanism to sensitize cells to anticancer therapy. However, we observed that GI-ME-N cells, a neuroblastoma cell line without MYCN amplification, are able to survive even if GSH-depleted by l-buthionine-(S,R)-sulfoximine (BSO). Here, we show that in GI-ME-N cells, BSO activates Nrf2 and up-regulates heme oxygenase-1 (HO-1). Silencing of Nrf2 restrained HO-1 induction by BSO. Inhibition of HO-1 and silencing of Nrf2 or HO-1 sensitized GI-ME-N cells to BSO, leading to reactive oxygen/nitrogen species overproduction and decreasing viability. Moreover, targeting the Nrf2/HO-1 axis sensitized GI-ME-N cells to etoposide more than GSH depletion. Therefore, we have provided evidence that in GI-ME-N cells, the Nrf2/HO-1 axis plays a crucial role as a protective factor against cellular stress, and we suggest that the inhibition of Nfr2/HO-1 signaling should be considered as a central target in the clinical battle against neuroblastoma.

Original languageEnglish
Pages (from-to)488-496
Number of pages9
JournalFree Radical Biology and Medicine
Volume52
Issue number2
DOIs
Publication statusPublished - Jan 15 2012

Keywords

  • Cancer
  • Etoposide
  • Free radicals
  • Glutathione
  • Heme oxygenase-1
  • Neuroblastoma
  • Nrf2
  • Oxidative stress

ASJC Scopus subject areas

  • Biochemistry
  • Physiology (medical)

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  • Cite this

    Furfaro, A. L., MacAy, J. R. Z., Marengo, B., Nitti, M., Parodi, A., Fenoglio, D., Marinari, U. M., Pronzato, M. A., Domenicotti, C., & Traverso, N. (2012). Resistance of neuroblastoma GI-ME-N cell line to glutathione depletion involves Nrf2 and heme oxygenase-1. Free Radical Biology and Medicine, 52(2), 488-496. https://doi.org/10.1016/j.freeradbiomed.2011.11.007