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Mitogen-activated protein kinase signaling in drug-resistant neuroblastoma cells
1Department of Pharmacology, Wayne State University, Detroit, MI, USA.
Abstract:
Widespread inherent or acquired resistance to cytotoxic drugs is a major limitation to chemotherapy. There are many mechanisms that contribute to such resistance. In neuroblastomas there is evidence that acquired drug resistance may be associated with altered response to growth factor signals. The ubiquitous mitogen-activated protein kinase (MAPk) cascade, which transmits growth factor signals from the cell membrane to the nucleus, provides a principal mechanism for regulation of cell cycle progression and proliferation. We have shown that there is a relationship between acquired drug resistance in human neuroblastoma cells to doxorubicin, a topoisomerase-2 inhibitor, and to MDL-28842, an inhibitor of S-adenosylhomocysteine hydrolase, and reductions in the activation and nuclear translocation of MAPk.
Insights
Acquired resistance to chemotherapy drugs in neuroblastoma is linked to altered growth factor signaling. Specifically, reduced mitogen-activated protein kinase (MAPk) activation and nuclear translocation correlate with drug resistance.
Area of Science:
- Oncology
- Molecular Biology
- Cell Signaling
Background:
- Chemotherapy resistance is a significant challenge in cancer treatment.
- Neuroblastomas can develop acquired resistance to cytotoxic drugs.
- Growth factor signaling pathways, like the MAPk cascade, regulate cell proliferation.
Purpose of the Study:
- To investigate the relationship between acquired drug resistance in neuroblastoma cells and the mitogen-activated protein kinase (MAPk) pathway.
- To explore the role of MAPk activation and nuclear translocation in chemoresistance.
Main Methods:
- Utilized human neuroblastoma cell lines.
- Assessed drug resistance to doxorubicin (topoisomerase-2 inhibitor) and MDL-28842 (S-adenosylhomocysteine hydrolase inhibitor).
- Measured activation and nuclear translocation of MAPk.
Main Results:
- Acquired resistance to doxorubicin and MDL-28842 was observed in neuroblastoma cells.
- A correlation was found between this drug resistance and reduced MAPk activation.
- Reduced nuclear translocation of MAPk was also associated with acquired chemoresistance.
Conclusions:
- Altered response to growth factor signals, specifically involving the MAPk pathway, is implicated in acquired chemoresistance in neuroblastoma.
- MAPk pathway dysregulation may represent a therapeutic target for overcoming drug resistance in neuroblastoma.