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.
Highlights
Cell ability to adapt to oxidative stress by detoxifying reactive oxygen species (ROS) and toxic molecules has been demonstrated to play a role in the failure of different anticancer therapies [1, 2]
In order to show the involvement of nuclear factor erythroid 2-related factor 2 (Nrf2)-dependent antioxidant responses in cell resistance to BTZ, the mRNA expression and the protein levels of heme oxygenase 1 (HO-1), γ-glutamylcysteine ligase and the transporter for cysteine (x-CT) have been measured
In this work we show the crucial role played by Nrf2, HO-1 and GSH, in the development of chemoresistance in highly aggressive neuroblastoma (NB) cells treated with bortezomib
Summary
Cell ability to adapt to oxidative stress by detoxifying reactive oxygen species (ROS) and toxic molecules has been demonstrated to play a role in the failure of different anticancer therapies [1, 2]. The imbalance of redox state, induced by different antitumour drugs, can be counteracted by the up-regulation of antioxidants, leading to tumour cell survival. The nuclear factor erythroid 2-related factor 2 (Nrf2) is a transcription factor primarly involved in cell adaption to stress [9]. Toxic molecules and oxidative insults can activate Nrf inducing the transcription of a plethora of antioxidant and detoxifying genes [10], among which there are HO-1, both the modifier (GCLM) and the catalytic (GCLC) subunits of γ- glutamylcysteine ligase (GCL), the first rate-limiting enzyme in the synthesis of GSH, and the cysteine/glutamate transporter x-CT [11]
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