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

• Published in: Free radical biology & medicine 2012-01, Vol.52 (2), p.488-496
• Main Authors: Furfaro, Anna Lisa, Macay, José Raúl Zumba, Marengo, Barbara, Nitti, Mariapaola, Parodi, Alessia, Fenoglio, Daniela, Marinari, Umberto Maria, Pronzato, Maria Adelaide, Domenicotti, Cinzia, Traverso, Nicola
• Format: Article
• Language: English
• Subjects: Antineoplastic Agents, Phytogenic - pharmacology; Buthionine Sulfoximine - pharmacology; Cancer; Cell Line, Tumor; Cell Proliferation - drug effects; Cell survival; Cell Survival - drug effects; cell viability; Drug Resistance, Neoplasm; Etoposide; Etoposide - pharmacology; Free radicals; Gene Expression - drug effects; Gene Knockdown Techniques; Glutamate-Cysteine Ligase - antagonists & inhibitors; Glutamate-Cysteine Ligase - metabolism; Glutathione; Glutathione - deficiency; Glutathione - metabolism; heme oxygenase (biliverdin-producing); Heme oxygenase (decyclizing); Heme oxygenase-1; Heme Oxygenase-1 - antagonists & inhibitors; Heme Oxygenase-1 - genetics; Heme Oxygenase-1 - metabolism; Humans; neoplasms; Neuroblastoma; Neuroblastoma cells; NF-E2-Related Factor 2 - metabolism; Nitrogen; Nrf2; Oxidative Stress; Oxygen; Protoporphyrins - pharmacology; Reactive Nitrogen Species - metabolism; reactive oxygen species; Reactive Oxygen Species - metabolism; therapeutics
• ISSN: 0891-5849; 1873-4596
• DOI: 10.1016/j.freeradbiomed.2011.11.007

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. [Display omitted] ► GI-ME-N neuroblastoma cell survival is independent from GSH depletion by BSO. ► BSO activates Nrf2 and up-regulates heme oxygenase-1 (HO-1) in GI-ME-N cells. ► Inhibition of HO-1 and silencing of Nrf2 or HO-1 sensitizes GI-ME-N cells to BSO. ► Inhibition of Nrf2/HO-1 axis sensitizes GI-ME-N cells to etoposide more than BSO. ► Inhibition Nfr2/HO-1 should be a potential target in neuroblastoma therapy.