P2X7 receptor isoform B is a key drug resistance mediator for neuroblastoma
Vanessa Fernandes Arnaud-Sampaio1, Carolina Adriane Bento1, Talita Glaser1
1Biochemistry Department, Institute of Chemistry, University of Sao Paulo, Sao Paulo, SP, Brazil.
Abstract:
Drug resistance is a major challenge for all oncological treatments that involve the use of cytotoxic agents. Recent therapeutic alternatives cannot circumvent the ability of cancer cells to adapt or alter the natural selection of resistant cells, so the problem persists. In neuroblastoma, recurrence can occur in up to 50% of high-risk patients. Therefore, the identification of novel therapeutic targets capable of modulating survival or death following classical antitumor interventions is crucial to address this problem. In this study, we investigated the role of the P2X7 receptor in chemoresistance. Here, we elucidated the contributions of P2X7 receptor A and B isoforms to neuroblastoma chemoresistance, demonstrating that the B isoform favors resistance through a combination of mechanisms involving drug efflux via MRP-type transporters, resistance to retinoids, retaining cells in a stem-like phenotype, suppression of autophagy, and EMT induction, while the A isoform has opposite and complementary roles.
Insights
The P2X7 receptor B isoform promotes neuroblastoma chemoresistance by enhancing drug efflux and stem-like properties. The P2X7 receptor A isoform plays opposing roles, offering potential therapeutic avenues.
Area of Science:
- Oncology
- Molecular Biology
- Cell Biology
Background:
- Drug resistance is a significant obstacle in cancer therapy, particularly in neuroblastoma where recurrence rates are high.
- Existing treatments struggle to overcome cancer cell adaptation and the selection of resistant cells.
- Novel therapeutic targets are needed to overcome chemoresistance and improve patient outcomes.
Purpose of the Study:
- To investigate the role of the P2X7 receptor in mediating chemoresistance in neuroblastoma.
- To elucidate the specific contributions of P2X7 receptor isoforms A and B to drug resistance.
Main Methods:
- Investigated the functional roles of P2X7 receptor isoforms A and B in neuroblastoma cells.
- Analyzed mechanisms including drug efflux, retinoid resistance, stem-like phenotype, autophagy suppression, and epithelial-mesenchymal transition (EMT).
Main Results:
- The P2X7 receptor B isoform was found to promote chemoresistance through multiple mechanisms.
- These mechanisms include enhanced drug efflux via MRP transporters, resistance to retinoids, maintenance of a stem-like phenotype, suppressed autophagy, and induced EMT.
- The P2X7 receptor A isoform exhibited opposite and complementary functions to the B isoform.
Conclusions:
- The P2X7 receptor isoforms differentially regulate neuroblastoma chemoresistance.
- P2X7 receptor B isoform promotes resistance, while P2X7 receptor A isoform may counteract it.
- Targeting P2X7 receptor isoforms presents a potential strategy to overcome chemoresistance in neuroblastoma.
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