title: Role of Nrf2, HO-1 and GSH in Neuroblastoma Cell Resistance to Bortezomib.
abstract: The activation of Nrf2 has been demonstrated to play a crucial role in cancer cell resistance to different anticancer therapies. The inhibition of proteasome activity has been proposed as a chemosensitizing therapy but the activation of Nrf2 could reduce its efficacy. Using the highly chemoresistant neuroblastoma cells HTLA-230, here we show that the strong reduction in proteasome activity, obtained by using low concentration of bortezomib (BTZ, 2.5 nM), fails in reducing cell viability. BTZ treatment favours the binding of Nrf2 to the ARE sequences in the promoter regions of target genes such as heme oxygenase 1 (HO-1), the modulatory subunit of γ-glutamylcysteine ligase (GCLM) and the transporter for cysteine (x-CT), enabling their transcription. GSH level is also increased after BTZ treatment. The up-regulation of Nrf2 target genes is responsible for cell resistance since HO-1 silencing and GSH depletion synergistically decrease BTZ-treated cell viability. Moreover, cell exposure to all-trans-Retinoic acid (ATRA, 3 μM) reduces the binding of Nrf2 to the ARE sequences, decreases HO-1 induction and lowers GSH level increasing the efficacy of bortezomib. These data suggest the role of Nrf2, HO-1 and GSH as molecular targets to improve the efficacy of low doses of bortezomib in the treatment of malignant neuroblastoma.
authors.affiliation: Giannina Gaslini Institute, Via Gerolamo Gaslini 5, 16147, Genova, Italy.
authors.forename: A L
authors.initials: AL
authors.lastname: Furfaro
authors.affiliation: Department of Experimental Medicine, University of Genoa, Via L.B. Alberti 2, 16132, Genova, Italy.
authors.forename: S
authors.initials: S
authors.lastname: Piras
authors.affiliation: Department of Experimental Medicine, University of Genoa, Via L.B. Alberti 2, 16132, Genova, Italy.
authors.forename: C
authors.initials: C
authors.lastname: Domenicotti
authors.affiliation: Center of Excellence for Biomedical Research, Department of Internal Medicine, University of Genoa, 16132, Genova, Italy.
authors.forename: D
authors.initials: D
authors.lastname: Fenoglio
authors.affiliation: IRCCS-Istituto di Ricerche Farmacologiche "Mario Negri", Via Giuseppe La Masa 19, 20156, Milano, Italy.
authors.forename: A
authors.initials: A
authors.lastname: De Luigi
authors.affiliation: IRCCS-Istituto di Ricerche Farmacologiche "Mario Negri", Via Giuseppe La Masa 19, 20156, Milano, Italy.
authors.forename: M
authors.initials: M
authors.lastname: Salmona
authors.affiliation: Bambino Gesù Children's Hospital, IRCCS, Piazza S. Onofrio 4, 00165, Roma, Italy.
authors.forename: L
authors.initials: L
authors.lastname: Moretta
authors.affiliation: Department of Experimental Medicine, University of Genoa, Via L.B. Alberti 2, 16132, Genova, Italy.
authors.forename: U M
authors.initials: UM
authors.lastname: Marinari
authors.affiliation: Department of Experimental Medicine, University of Genoa, Via L.B. Alberti 2, 16132, Genova, Italy.
authors.forename: M A
authors.initials: MA
authors.lastname: Pronzato
authors.affiliation: Department of Experimental Medicine, University of Genoa, Via L.B. Alberti 2, 16132, Genova, Italy.
authors.forename: N
authors.initials: N
authors.lastname: Traverso
authors.affiliation: Department of Experimental Medicine, University of Genoa, Via L.B. Alberti 2, 16132, Genova, Italy.
authors.forename: M
authors.initials: M
authors.lastname: Nitti
mesh_terms: D027182:Amino Acid Transport System y+ / Q000378:metabolism; D061745:Antioxidant Response Elements / Q000235:genetics; D000069286:Bortezomib / Q000494:pharmacology*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D020868:Gene Silencing / Q000187:drug effects; D005721:Glutamate-Cysteine Ligase / Q000235:genetics / Q000378:metabolism; D005978:Glutathione / Q000378:metabolism*; D051547:Heme Oxygenase-1 / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D051267:NF-E2-Related Factor 2 / Q000378:metabolism*; D009447:Neuroblastoma / Q000235:genetics / Q000378:metabolism*; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D021122:Protein Subunits / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D014158:Transcription, Genetic / Q000187:drug effects; D014212:Tretinoin / Q000494:pharmacology; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D027182:Amino Acid Transport System y+; D051267:NF-E2-Related Factor 2; D021122:Protein Subunits; D012333:RNA, Messenger; C118895:SLC7A11 protein, human; D014212:Tretinoin; D000069286:Bortezomib; D051547:Heme Oxygenase-1; D046988:Proteasome Endopeptidase Complex; D005721:Glutamate-Cysteine Ligase; D005978:Glutathione