Selenium is an essential element that is specifically incorporated as selenocystein into selenoproteins. It is a potent modulator of eukaryotic cell growth with strictly concentration-dependant effects. Lower concentrations are necessary for cell survival and growth, whereas higher concentrations inhibit growth and induce cell death. It is well established that selenium has cancer preventive effects, and several studies also have shown that it has strong anticancer effects with a selective cytotoxicity on malignant drug-resistant cells while only exerting marginal effects on normal and benign cells. This cancer-specific cytotoxicity is likely explained by high affinity selenium uptake dependent on proteins connected to multidrug resistance. One of the most studied selenoproteins in cancer is thioredoxin reductase (TrxR) that has important functions in neoplastic growth and is an important component of the resistant phenotype. Several reports have shown that TrxR is induced in tumor cells and pre-neoplastic cells, and several commonly used drugs interact with the protein. In this review, we summarize the current knowledge of selenium as a potent preventive and tumor selective anticancer drug, and we also discuss the potential of using the expression and modulation of the selenoprotein TrxR in the diagnostics and treatment of cancer.

Reactive oxygen species (ROS) are generated as toxic by-products of aerobic metabolism, but are also essential biomolecules in cell signaling. The thioredoxin (Trx) system is a major enzymatic system modulating ROS levels and is important for redox regulation of cellular function. It consists of Trx and thioredoxin reductase (TrxR), which reduces Trx using NADPH. Most, if not all, of the functions of Trx depend on the activity of TrxR. Mammalian TrxR enzymes are selenoproteins with broad substrate specificities, and alteration of cytosolic TrxR1 expression and activity is likely to be an important determinant for the control of cellular redox regulation. TrxR1 activity in cells seems to be modulated by an intricate interplay, involving a housekeeping type promoter in combination with alternative splice variants and transcriptional start sites, posttranscriptional regulation through AU-rich elements, inactivation by electrophilic agents and by itself modulating the effects of several key signaling molecules. TrxR1 activity is also intimately linked with several aspects of selenium metabolism, and hence selenoprotein function in general. Here, we summarize the current knowledge of these different levels of TrxR1 regulation in diverse cell types and in response to growth and signaling events.

The selenium salt selenite (SeO3 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.2Ϫ ) efficiently inhibits the growth of malignant cells and studies suggest an inverse relationship between resistance to cytotoxic drugs and sensitivity to selenite (SeO 3 2Ϫ ) (1, 2). A major mechanism of selenite cytotoxicity is thought to be the generation of oxidative stress through intracellular redox cycling of the selenium metabolite selenide with oxygen and cellular thiols, producing nonstoichiometric amounts of superoxide and cellular disulfides. The induction of oxidative stress and consequent apoptosis has been demonstrated in numerous cancer cell lines (2-8), but why this occurs only in malignant cells at easily achievable selenium plasma concentrations remains unclear.With the assumption that the mechanistic explanation is intracellular, studies on differences in cellular uptake have been neglected. Already in the 1960s, selenite (SeO 3 2Ϫ ) was being used experimentally as a tumor-localizing agent. Neoplasms could be detected in brain and thorax in human subjects through i.v. administration of radioactive selenite ( 75 Se) (9). Although at that time the cancer-specific cytotoxic effects of selenite were unknown, and low doses were used (approximately in the nM range in blood) (9), early findings clearly demonstrated that cancer cells enrich selenium in vivo. These findings, combined with current knowledge of selenite's toxic effects on malignant cells, raise the possibility of a cancer-specific high-affinity selenium uptake mechanism that might explain cancer-specific selenite cytotoxicity at therapeutic selenite concentrations (M range).In yeast, millimolar tolerance to selenite can be reduced to the micromolar range by the presence of excessive thiols in the growth medium through high-affinity uptake of a more reduced form of selenite, possibly selenide (10). High-affinity uptake of selenium through the addition of extracellular thiols also has been demonstrated in a keratinocyte model (11) using nanomolar concentrations of selenite. Selenium uptake was prevented in keratinocytes by the ...

Malignant mesothelioma cells differentiate into sarcomatoid or epithelioid phenotypes. The sarcomatoid cell type is more resistant to chemotherapy and gives a worse prognosis. We have investigated whether selenite alone and in combination with doxorubicin induced apoptosis in variously differentiated mesothelioma cells. Selenite in concentrations that could potentially be administered to patients strongly inhibited the growth of the sarcomatoid mesothelioma cells (IC50 = 7.5 microM), whereas epithelioid cells were more sensitive to doxorubicin. Benign mesothelial cells remained largely unaffected. Selenite potentiated doxorubicin treatment. Apoptosis was the dominating mode of cell death. The toxicity of selenite was mediated by oxidative stress. Furthermore the activity of the thioredoxin system was directly dependent on the concentration of selenite. This offers a possible mechanism of action of selenite treatment. Our findings suggest that selenite is a promising new drug for the treatment of malignant mesothelioma.

Human thioredoxin reductase 1 (TrxR1, the TXNRD1 gene product) is a ubiquitously expressed selenoprotein with many important redox regulatory functions. In this study, we have further characterized the recently identified core promoter region of TXNRD1. One critical Sp1/Sp3 site was found to be important in A549 and HeLa cells, whereas another Sp1/Sp3 site and one Oct1 site bound transcription factors but were, nonetheless, dispensable for transcription. We also experimentally identified several 5'-region TXNRD1 transcript variants using 5'-RACE with cDNA derived from different tissues, and we analyzed all available TXNRD1-derived EST sequences. The results show that the core promoter governs transcription of the clear majority of TXNRD1 transcripts but also that alternative promoters may be activated under rare conditions or in specific cell types. Furthermore, extensive alternative splicing occured in the 5' region of TXNRD1. In total, 21 different transcripts were identified, potentially encoding five isoforms of TrxR1 carrying alternative N-terminal domains. One isoform encompassed a glutaredoxin domain, whereas another encoded a predicted mitochondrial localization signal. These results reveal that the human thioredoxin system is intriguingly complex. Cell-specific transcription of the TXNRD1 gene encoding different isoforms of TrxR1 must be taken into account to fully understand the functions of the human thioredoxin system.

The thioredoxin family of proteins is important for growth and differentiation of lung cancer cells. The correlation with differentiation and proliferation of these enzymes makes them promising predictive/diagnostic markers.

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