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Antiepileptic drugs reduce the efficacy of methotrexate chemotherapy through accelerated degradation of the reduced folate carrier by the ubiquitin-proteasome pathway
Chemotherapy, 09/07/2011
Clinical Article
Halwachs S et al. – These results demonstrate that PB treatment causes downregulation of Rfc1 activity through PKC-dependent accelerated degradation of the Rfc1 protein by the ubiqutin-proteasome pathway. This regulatory mechanism may therefore involve clinically relevant drug resistance in patients concurrently receiving MTX and enzyme-inducing antiepileptic drugs.
Results- Protein turnover assays using hepatocytoma cells demonstrated that Rfc1 is long-lived protein that is mainly degraded by ubiquitin-proteasome proteolytic pathway under basal conditions
- Pretreatment with PB significantly reduced Rfc1-mediated MTX uptake and shortened carrier protein half-life
- Effect abolished by specific PKC inhibitor Gö6976
- Inhibition of proteasomes with MG-132 significantly elevated Rfc1 protein levels and induced colocalization of Rfc1 and ubiquitin particularly in submembranous cellular compartments
- Demonstrated that PB treatment resulted in enhanced levels of Rfc1 polyubiquitin conjugates
