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Role of Nrf2, HO-1 and GSH in Neuroblastoma Cell Resistance to Bortezomib
A L Furfaro1, S Piras2, C Domenicotti2
1Giannina Gaslini Institute, Via Gerolamo Gaslini 5, 16147, Genova, Italy.
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.
Insights
Low-dose bortezomib (BTZ) activates Nrf2, increasing cancer cell resistance by upregulating heme oxygenase 1 (HO-1) and glutathione (GSH). Targeting Nrf2, HO-1, and GSH may enhance BTZ efficacy in neuroblastoma.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- Nuclear factor erythroid 2-related factor 2 (Nrf2) activation confers cancer cell resistance to therapies.
- Proteasome inhibition is a chemosensitizing strategy, but Nrf2 activation may limit its effectiveness.
Purpose of the Study:
- To investigate the role of Nrf2 activation in mediating resistance to low-dose bortezomib (BTZ) in neuroblastoma.
- To explore Nrf2, heme oxygenase 1 (HO-1), and glutathione (GSH) as potential therapeutic targets to overcome BTZ resistance.
Main Methods:
- Utilized chemoresistant neuroblastoma cells (HTLA-230) treated with low-dose bortezomib (BTZ).
- Assessed Nrf2 binding to antioxidant response elements (AREs), transcription of target genes (HO-1, GCLM, x-CT), and intracellular GSH levels.
- Investigated the effects of HO-1 silencing, GSH depletion, and all-trans-Retinoic acid (ATRA) treatment on cell viability and BTZ efficacy.
Main Results:
- Low-dose BTZ (2.5 nM) failed to reduce neuroblastoma cell viability and increased Nrf2 binding to AREs, leading to upregulated HO-1, GCLM, and x-CT expression and elevated GSH levels.
- Silencing HO-1 and depleting GSH synergistically reduced BTZ-treated cell viability, confirming their role in resistance.
- All-trans-Retinoic acid (ATRA) treatment decreased Nrf2 binding, HO-1 induction, and GSH levels, thereby enhancing BTZ efficacy.
Conclusions:
- Nrf2, HO-1, and GSH mediate resistance to low-dose bortezomib in malignant neuroblastoma.
- Targeting the Nrf2/HO-1/GSH pathway, potentially with agents like ATRA, could improve bortezomib treatment efficacy.
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