title: HO-1 up-regulation: a key point in high-risk neuroblastoma resistance to bortezomib.
abstract: High-risk neuroblastoma (NB) is characterized by the development of chemoresistance, and bortezomib (BTZ), a selective inhibitor of proteasome, has been proposed in order to overcome drug resistance. Considering the involvement of the nuclear factor-erythroid-derived 2-like 2 (Nrf2) and heme oxygenase-1 (HO-1) in the antioxidant and detoxifying ability of cancer cells, in this study we have investigated their role in differently aggressive NB cell lines treated with BTZ, focusing on the modulation of HO-1 to improve sensitivity to therapy. We have shown that MYCN amplified HTLA-230 cells were slightly sensitive to BTZ treatment, due to the activation of Nrf2 that led to an impressive up-regulation of HO-1. BTZ-treated HTLA-230 cells down-regulated p53 and up-regulated p21, favoring cell survival. The inhibition of HO-1 activity obtained by Zinc (II) protoprophyrin IX (ZnPPIX) was able to significantly increase the pro-apoptotic effect of BTZ in a p53- and p21-independent way. However, MYCN non-amplified SH-SY5Y cells showed a greater sensitivity to BTZ in relation to their inability to up-regulate HO-1. Therefore, we have shown that HO-1 inhibition improves the sensitivity of aggressive NB to proteasome inhibition-based therapy, suggesting that HO-1 up-regulation can be used as a marker of chemoresistance in NB. These results open up a new scenario in developing a combined therapy to overcome chemoresistance in high-risk neuroblastoma.
authors.affiliation: Department of Experimental Medicine, University of Genoa, 2, L.B. Alberti Street, I-16132 Genoa, Italy. Electronic address: annalisa.furfaro@unige.it.
authors.forename: Anna Lisa
authors.initials: AL
authors.lastname: Furfaro
authors.affiliation: Department of Experimental Medicine, University of Genoa, 2, L.B. Alberti Street, I-16132 Genoa, Italy. Electronic address: piras.sabri@tiscali.it.
authors.forename: Sabrina
authors.initials: S
authors.lastname: Piras
authors.affiliation: Department of Experimental Medicine, University of Genoa, 2, L.B. Alberti Street, I-16132 Genoa, Italy. Electronic address: Mario.Passalacqua@unige.it.
authors.forename: Mario
authors.initials: M
authors.lastname: Passalacqua
authors.affiliation: Department of Experimental Medicine, University of Genoa, 2, L.B. Alberti Street, I-16132 Genoa, Italy. Electronic address: Cinzia.Domenicotti@unige.it.
authors.forename: Cinzia
authors.initials: C
authors.lastname: Domenicotti
authors.affiliation: Center of Excellence for Biomedical Research, Department of Internal Medicine, University of Genoa, 16132 Genoa, Italy. Electronic address: alessiaparodi@yahoo.it.
authors.forename: Alessia
authors.initials: A
authors.lastname: Parodi
authors.affiliation: Center of Excellence for Biomedical Research, Department of Internal Medicine, University of Genoa, 16132 Genoa, Italy. Electronic address: Daniela.Fenoglio@unige.it.
authors.forename: Daniela
authors.initials: D
authors.lastname: Fenoglio
authors.affiliation: Department of Experimental Medicine, University of Genoa, 2, L.B. Alberti Street, I-16132 Genoa, Italy. Electronic address: maidep@unige.it.
authors.forename: Maria Adelaide
authors.initials: MA
authors.lastname: Pronzato
authors.affiliation: Department of Experimental Medicine, University of Genoa, 2, L.B. Alberti Street, I-16132 Genoa, Italy. Electronic address: umm@unige.it.
authors.forename: Umberto Maria
authors.initials: UM
authors.lastname: Marinari
authors.affiliation: Giannina Gaslini Institute, 16147 Genoa, Italy. Electronic address: Lorenzo.Moretta@ospedale-gaslini.ge.it.
authors.forename: Lorenzo
authors.initials: L
authors.lastname: Moretta
authors.affiliation: Department of Experimental Medicine, University of Genoa, 2, L.B. Alberti Street, I-16132 Genoa, Italy. Electronic address: Nicola.Traverso@unige.it.
authors.forename: Nicola
authors.initials: N
authors.lastname: Traverso
authors.affiliation: Department of Experimental Medicine, University of Genoa, 2, L.B. Alberti Street, I-16132 Genoa, Italy. Electronic address: Mariapaola.Nitti@unige.it.
authors.forename: Mariapaola
authors.initials: M
authors.lastname: Nitti
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D001897:Boronic Acids / Q000494:pharmacology*; D000069286:Bortezomib; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000032:analysis; D019008:Drug Resistance, Neoplasm; D051547:Heme Oxygenase-1 / Q000032:analysis / Q000037:antagonists & inhibitors / Q000502:physiology*; D006801:Humans; D000071447:N-Myc Proto-Oncogene Protein; D051267:NF-E2-Related Factor 2 / Q000502:physiology; D009447:Neuroblastoma / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D009687:Nuclear Proteins / Q000032:analysis; D015513:Oncogene Proteins / Q000032:analysis; D011719:Pyrazines / Q000494:pharmacology*; D012306:Risk; D015854:Up-Regulation
chemical_list: D000970:Antineoplastic Agents; D001897:Boronic Acids; C493956:CDKN1A protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; C459801:MYCN protein, human; D000071447:N-Myc Proto-Oncogene Protein; D051267:NF-E2-Related Factor 2; C495635:NFE2L2 protein, human; D009687:Nuclear Proteins; D015513:Oncogene Proteins; D011719:Pyrazines; D000069286:Bortezomib; D051547:Heme Oxygenase-1
keywords: Chemoresistance; Heme oxygenase-1; Neuroblastoma; Redox signaling