title: Resistance of neuroblastoma GI-ME-N cell line to glutathione depletion involves Nrf2 and heme oxygenase-1.
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.
authors.affiliation: Department of Experimental Medicine, University of Genova, 16132 Genova, Italy.
authors.forename: Anna Lisa
authors.initials: AL
authors.lastname: Furfaro
authors.forename: José Raúl Zumba
authors.initials: JR
authors.lastname: Macay
authors.forename: Barbara
authors.initials: B
authors.lastname: Marengo
authors.forename: Mariapaola
authors.initials: M
authors.lastname: Nitti
authors.forename: Alessia
authors.initials: A
authors.lastname: Parodi
authors.forename: Daniela
authors.initials: D
authors.lastname: Fenoglio
authors.forename: Umberto Maria
authors.initials: UM
authors.lastname: Marinari
authors.forename: Maria Adelaide
authors.initials: MA
authors.lastname: Pronzato
authors.forename: Cinzia
authors.initials: C
authors.lastname: Domenicotti
authors.forename: Nicola
authors.initials: N
authors.lastname: Traverso
mesh_terms: D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology; D019328:Buthionine Sulfoximine / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D019008:Drug Resistance, Neoplasm; D005047:Etoposide / Q000494:pharmacology; D015870:Gene Expression / Q000187:drug effects; D055785:Gene Knockdown Techniques; D005721:Glutamate-Cysteine Ligase / Q000037:antagonists & inhibitors / Q000378:metabolism; D005978:Glutathione / Q000172:deficiency* / Q000378:metabolism; D051547:Heme Oxygenase-1 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D051267:NF-E2-Related Factor 2 / Q000378:metabolism*; D009447:Neuroblastoma; D018384:Oxidative Stress; D011524:Protoporphyrins / Q000494:pharmacology; D026361:Reactive Nitrogen Species / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D051267:NF-E2-Related Factor 2; D011524:Protoporphyrins; D026361:Reactive Nitrogen Species; D017382:Reactive Oxygen Species; C017803:zinc protoporphyrin; D019328:Buthionine Sulfoximine; D005047:Etoposide; C496541:HMOX1 protein, human; D051547:Heme Oxygenase-1; D005721:Glutamate-Cysteine Ligase; D005978:Glutathione