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Melanoma coordinates general and cell-specific mechanisms to promote methotrexate resistance.
MedLine Citation:
PMID:  22484375     Owner:  NLM     Status:  Publisher    
Abstract/OtherAbstract:
Melanoma, the most aggressive form of skin cancer, is notoriously resistant to all current modalities of cancer therapy, including to the drug methotrexate. Melanosomal sequestration and cellular exportation of methotrexate have been proposed to be important melanoma-specific mechanisms that contribute to the resistance of melanoma to methotrexate. In addition, other mechanisms of resistance that are present in most epithelial cancer cells are also operative in melanoma. This report elucidates how melanoma orchestrates these mechanisms to become extremely resistant to methotrexate, where both E2F1 and checkpoint kinase 1 (Chk1), two molecules with dual roles in survival/apoptosis, play prominent roles. The results indicated that MTX induced the depletion of dihydrofolate in melanoma cells, which stimulated the transcriptional activity of E2F1. The elevate expression of dihydrofolate reductase and thymidylate synthase, two E2F1-target genes involved in folate metabolism and required for G(1) progression, favored dTTP accumulation, which promoted DNA single strand breaks and the subsequent activation of Chk1. Under these conditions, melanoma cells are protected from apoptosis by arresting their cell cycle in S phase. Excess of dTTP could also inhibit E2F1-mediated apoptosis in melanoma cells.
Authors:
Magalí Sáez-Ayala; María Piedad Fernández-Pérez; María F Montenegro; Luis Sánchez-Del-Campo; Soledad Chazarra; Antonio Piñero-Madrona; Juan Cabezas-Herrera; José Neptuno Rodríguez-López
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Publication Detail:
Type:  JOURNAL ARTICLE     Date:  2012-3-29
Journal Detail:
Title:  Experimental cell research     Volume:  -     ISSN:  1090-2422     ISO Abbreviation:  -     Publication Date:  2012 Mar 
Date Detail:
Created Date:  2012-4-9     Completed Date:  -     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  0373226     Medline TA:  Exp Cell Res     Country:  -    
Other Details:
Languages:  ENG     Pagination:  -     Citation Subset:  -    
Copyright Information:
Copyright © 2012. Published by Elsevier Inc.
Affiliation:
Department of Biochemistry and Molecular Biology A, School of Biology, University of Murcia, Murcia, Spain.
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