Apr 10, 2012

Melanoma coordinates general and cell-specific mechanisms to promote methotrexate resistance

Experimental Cell Research
Magali Sáez-AyalaJosé Neptuno Rodríguez-López

Abstract

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 dT...Continue Reading

  • References29
  • Citations9

References

  • References29
  • Citations9

Citations

Mentioned in this Paper

Malignant Neoplasm of Skin
Pathologic Cytolysis
CHEK2 wt Allele
Cell Cycle Progression
Metabolic Process, Cellular
Thymidine 5'-triphosphate, trisodium salt
Biochemical Pathway
Formicum acidum, formic acid, Homeopathic preparation
FOXN3 wt Allele
Histone antigen

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