Role of Nrf2, HO-1 and GSH in Neuroblastoma Cell Resistance to Bortezomib

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...

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Bibliographic Details
Published in:PloS one 2016-03, Vol.11 (3), p.e0152465-e0152465
Main Authors: Furfaro, A L, Piras, S, Domenicotti, C, Fenoglio, D, De Luigi, A, Salmona, M, Moretta, L, Marinari, U M, Pronzato, M A, Traverso, N, Nitti, M
Format: Article
Language:English
Subjects:
Activation
Adapter proteins
Amino Acid Transport System y+ - metabolism
Antioxidant Response Elements - genetics
Antioxidants
Binding
Biology and Life Sciences
Bortezomib
Bortezomib - pharmacology
Cancer
Cell Line, Tumor
Cell Survival - drug effects
Complications and side effects
Dosage and administration
Dose-Response Relationship, Drug
Drug Resistance, Neoplasm - drug effects
Drug therapy
Effectiveness
Gene expression
Gene Expression Regulation, Neoplastic - drug effects
Gene regulation
Gene sequencing
Gene Silencing - drug effects
Genes
Genetic aspects
Glutamate-Cysteine Ligase - genetics
Glutamate-Cysteine Ligase - metabolism
Glutathione
Glutathione - metabolism
Heme
Heme Oxygenase-1 - genetics
Heme Oxygenase-1 - metabolism
Humans
Inhibitor drugs
Medicine
Medicine and Health Sciences
Neuroblastoma
Neuroblastoma - genetics
Neuroblastoma - metabolism
Neuroblastoma cells
NF-E2-Related Factor 2 - metabolism
Oxidative stress
Oxygenase
Physiological aspects
Proteasome Endopeptidase Complex - metabolism
Proteasomes
Protein Subunits - genetics
Protein Subunits - metabolism
Research and analysis methods
Retinoic acid
RNA, Messenger - genetics
RNA, Messenger - metabolism
Rodents
Transcription
Transcription factors
Transcription, Genetic - drug effects
Tretinoin - pharmacology
Tumors
Up-Regulation - drug effects
γ-Glutamylcysteine
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Summary: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.
ISSN:1932-6203
1932-6203
DOI:10.1371/journal.pone.0152465