The critical role of alpha-folate receptor in the resistance of melanoma to methotrexate.
Although methotrexate (MTX) is an effective drug for several types of cancer, it is not active against melanoma. Experiments following methotrexate treatment indicated a reduced accumulation of the drug in the cytosolic compartment in melanoma cells, suggesting that the mechanisms that control the transport and retention of this drug could be altered in melanoma. For this reason, we analyzed the presence and function of folate receptor-alpha (FRalpha) in melanoma cells. In this study, we have identified the presence of FRalpha in normal and pathological melanocytes and demonstrated that MTX is preferentially transported through this receptor in melanoma cells. FRalpha-induced endocytic transport of MTX, together with drug melanosomal sequestration and cellular exportation, ensures reduced accumulation of this cytotoxic compound in intracellular compartments. The critical role of FRalpha in this mechanism of resistance and the therapeutic consequences of these findings are also discussed.
Sánchez-del-Campo
Luís
L
Department of Biochemistry and Molecular Biology A, School of Biology, University of Murcia, 30100 Murcia, Spain.
Montenegro
María F
MF
Cabezas-Herrera
Juan
J
Rodríguez-López
José Neptuno
JN
D000368:Aged; D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000737:chemistry / Q000627:therapeutic use*; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm; D004705:Endocytosis / Q000502:physiology; D058973:Folate Receptors, GPI-Anchored; D005492:Folic Acid / Q000737:chemistry / Q000378:metabolism; D006801:Humans; D008297:Male; D008544:Melanocytes / Q000166:cytology / Q000378:metabolism; D008545:Melanoma / Q000188:drug therapy / Q000378:metabolism; D020460:Melanosomes / Q000378:metabolism; D008727:Methotrexate / Q000737:chemistry / Q000627:therapeutic use*; D051379:Mice; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D011956:Receptors, Cell Surface / Q000235:genetics / Q000378:metabolism*
D000964:Antimetabolites, Antineoplastic; D002352:Carrier Proteins; D058973:Folate Receptors, GPI-Anchored; D020033:Protein Isoforms; D011956:Receptors, Cell Surface; D005492:Folic Acid; D008727:Methotrexate