Extracellular thiol-assisted selenium uptake dependent on the x c − cystine transporter explains the cancer-specific cytotoxicity of selenite
- 7 July 2009
- journal article
- Published by Proceedings of the National Academy of Sciences in Proceedings of the National Academy of Sciences of the United States of America
- Vol. 106 (27), 11400-11405
- https://doi.org/10.1073/pnas.0902204106
Abstract
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.This publication has 31 references indexed in Scilit:
- The xc− cystine/glutamate antiporter: a mediator of pancreatic cancer growth with a role in drug resistanceBritish Journal of Cancer, 2008
- The JNK signaling pathway is involved in sodium-selenite-induced apoptosis mediated by reactive oxygen in HepG2 cellsCancer Biology & Therapy, 2008
- The x cystine/glutamate antiporter: A potential target for therapy of cancer and other diseasesJournal of Cellular Physiology, 2008
- High affinity selenium uptake in a keratinocyte modelFEBS Letters, 2007
- Autocrine Glutamate Signaling Promotes Glioma Cell InvasionCancer Research, 2007
- The cystine/cysteine cycle: a redox cycle regulating susceptibility versus resistance to cell deathOncogene, 2007
- Selenium activates p53 and p38 pathways and induces caspase-independent cell death in cervical cancer cellsCell Biology and Toxicology, 2007
- Sodium Selenite Induces Superoxide-Mediated Mitochondrial Damage and Subsequent Autophagic Cell Death in Malignant Glioma CellsCancer Research, 2007
- Selenite induces apoptosis in sarcomatoid malignant mesothelioma cells through oxidative stressFree Radical Biology & Medicine, 2006
- Tumor-selective killing by selenite in patient-matched pairs of normal and malignant prostate cellsThe Prostate, 2006