Research: FURFARO and COLLEAGUES,

Listed in Issue 275

Abstract

FURFARO and COLLEAGUES, 1. Giannina Gaslini Institute, Via Gerolamo Gaslini 5, 16147, Genova, Italy; 2. Department of Experimental Medicine, University of Genoa, Via L.B. Alberti 2, 16132, Genova, Italy; 3. Center of Excellence for Biomedical Research, Department of Internal Medicine, University of Genoa, 16132, Genova, Italy; 4. IRCCS-Istituto di Ricerche Farmacologiche "Mario Negri", Via Giuseppe La Masa 19, 20156, Milano, Italy; 5. Bambino Gesù Children's Hospital, IRCCS, Piazza S. Onofrio 4, 00165, Roma, Italy analyzed at the molecular level Neuroblastoma Cell Resistance to Bortezomib (BTZ).

Background

The activation of Nrf2 (Nuclear factor-erythroid factor 2-related factor 2) [a critical transcription factor that regulates the expression of over 1000 genes in the cell under normal and stressed conditions.] has been demonstrated to play a crucial role in cancer cell resistance to different anticancer therapies.

Methodology

The inhibition of proteasome activity has been proposed as a chemo sensitizing therapy but the activation of Nrf2 could reduce its efficacy.

Results

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 [an anti-cancer medication used to treat multiple myeloma and mantle cell lymphoma], 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.

Conclusion

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.

References

Furfaro AL1, Piras S2, Domenicotti C2, Fenoglio D3, De Luigi A4, Salmona M4, Moretta L5, Marinari UM2, Pronzato MA2, Traverso N2, Nitti M2. Role of Nrf2, HO-1 and GSH in Neuroblastoma Cell Resistance to Bortezomib. PLoS One. 11(3):e0152465. Mar 29 2016. doi: 10.1371/journal.pone.0152465. eCollection 2016.

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