Extracellular thiol-assisted selenium uptake dependent on the x(c)- cystine transporter explains the cancer-specific cytotoxicity of selenite.
The selenium salt selenite (SeO(3)(2-)) is cytotoxic in low to moderate concentrations, with a remarkable specificity for cancer cells resistant to conventional chemotherapy. Our data show that selenium uptake and accumulation, rather than intracellular events, are crucial to the specific selenite cytotoxicity observed in resistant cancer cells. We show that selenium uptake depends on extracellular reduction, and that the extracellular environment is a key factor specific to selenite cytotoxicity. The extracellular reduction is mediated by cysteine, and the efficacy is determined by the uptake of cystine by the x(c)(-) antiporter and secretion of cysteine by multidrug resistance proteins, both of which are frequently overexpressed by resistant cancer cells. This mechanism provides molecular evidence for the existence of an inverse relationship between resistance to conventional chemotherapy and sensitivity to selenite cytotoxicity, and highlights the great therapeutic potential in treating multidrug-resistant cancer.
Olm
Eric
E
Division of Pathology F46, Department of Laboratory Medicine, Karolinska Institutet, Stockholm SE-141 86, Sweden. eric.olm@ki.se
Fernandes
Aristi P
AP
Hebert
Christina
C
Rundlöf
Anna-Klara
AK
Larsen
Erik H
EH
Danielsson
Olof
O
Björnstedt
Mikael
M
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism; D027182:Amino Acid Transport System y+ / Q000378:metabolism*; D017920:Antiporters / Q000378:metabolism; D016923:Cell Death / Q000187:drug effects; D045744:Cell Line, Tumor; D003553:Cystine / Q000031:analogs & derivatives / Q000378:metabolism* / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D005110:Extracellular Space / Q000187:drug effects / Q000378:metabolism*; D005978:Glutathione / Q000031:analogs & derivatives / Q000494:pharmacology; D006801:Humans; D008175:Lung Neoplasms / Q000378:metabolism*; D008954:Models, Biological; D016566:Organoselenium Compounds / Q000494:pharmacology; D010084:Oxidation-Reduction / Q000187:drug effects; D012643:Selenium / Q000378:metabolism*; D018038:Sodium Selenite / Q000633:toxicity*; D013438:Sulfhydryl Compounds / Q000378:metabolism*
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D027182:Amino Acid Transport System y+; D017920:Antiporters; D016566:Organoselenium Compounds; C118895:SLC7A11 protein, human; D013438:Sulfhydryl Compounds; C009226:selenocystine; C017710:selenodiglutathione; D003553:Cystine; D005978:Glutathione; D012643:Selenium; D018038:Sodium Selenite