Dietary selenium has potent cancer prevention activity. Both low molecular weight selenocompounds and selenoproteins are implicated in this effect. Thioredoxin reductase 1 (TR1) is one of the major antioxidant and redox regulators in mammals that supports p53 function and other tumor suppressor activities. However, this selenium-containing oxidoreductase is also overexpressed in many malignant cells and has been proposed as a target for cancer therapy. To further assess the role of TR1 in the malignancy process, we used RNA interference technology to decrease its expression in mouse lung carcinoma (LLC1) cells. Stable transfection of LLC1 cells with a small interfering RNA construct that specifically targets TR1 removal manifested a reversal in the morphology and anchorageindependent growth properties of these cancer cells that made them similar to those of normal cells. The expression of at least two cancer-related protein mRNAs, Hgf and Opn1, were reduced dramatically in the TR1 knockdown cells. Mice injected with the TR1 knockdown showed a dramatic reduction in tumor progression and metastasis compared with those mice injected with the corresponding control vector. In addition, tumors that arose from injected TR1 knockdown cells lost the targeting construct, suggesting that TR1 is essential for tumor growth in mice. These observations provide direct evidence that the reduction of TR1 levels in malignant cells is antitumorigenic and suggest that the enzyme is a prime target for cancer therapy.There are 25 selenoproteins in humans and 24 in rodents (1), and of those with known functions, most serve as antioxidants (reviewed in Refs. 2 and 3). One of these selenoproteins, thioredoxin reductase 1 (TR1), 2 is one of the major antioxidant and redox regulators in mammalian cells. TR1 is an essential protein (4) that is expressed in all cell types and organs (2, 3), and the Sec moiety is essential for its activity (5, 6). Interestingly, it is overexpressed in many malignant cells (e.g. see Refs. 7-10). A variety of potent TR1 inhibitors have been shown to alter the cancer-related properties of tumors and numerous malignant cells (see Refs. 7-13 and references therein). For example, recently, a potent antitumor drug, 1,2-[bis (2-benzysoselenazolone-3(2H)-ketone)]ethane, was found to reverse the phenotype of five human carcinoma cell lines (13). Furthermore, reduction of TR1 activity in human hepatocellular carcinoma cells by transfection with TR1 antisense RNA inhibited cell growth (14). TR1 has therefore been implicated as a potential target for cancer therapy (e.g. see Refs. 7, 9, 10, and 15).On the other hand, TR1 is a selenoprotein that activates tumor suppressor p53 (16) and is specifically targeted by carcinogenic electrophiles (17,18). Dietary selenium also has potent cancer prevention activity (see Refs. 19 and 20 and references therein). These latter studies have implicated TR1 in tumor suppression, and thus, the overall role of TR1 in tumor progression remains unclear. To further assess the role of TR1 in tu...
Thioredoxin reductase 1 (TR1) is a major redox regulator in mammalian cells. As an important antioxidant selenoprotein, TR1 is thought to participate in cancer prevention, but is also known to be over-expressed in many cancer cells. Numerous cancer drugs inhibit TR1, and this protein has been proposed as a target for cancer therapy. We previously reported that reduction of TR1 levels in cancer cells reversed many malignant characteristics suggesting that deficiency in TR1 function is antitumorigenic. The molecular basis for TR1's role in cancer development, however, is not understood. Herein, we found that, among selenoproteins, TR1 is uniquely overexpressed in cancer cells and its knockdown in a mouse cancer cell line driven by oncogenic k-ras resulted in morphological changes characteristic of parental (normal) cells, without significant effect on cell growth under normal growth conditions. When grown in serum-deficient medium, TR1 deficient cancer cells lose self-sufficiency of growth, manifest a defective progression in their S phase and a decreased expression of DNA polymerase α, an enzyme important in DNA replication. These observations provide evidence that TR1 is critical for self-sufficiency in growth signals of malignant cells, that TR1 acts largely as a pro-cancer protein and it is indeed a primary target in cancer therapy.
Background: Selenium, a micronutrient whose deficiency in diet causes immune dysfunction and inflammatory disorders, is thought to exert its physiological effects mostly in the form of seleniumcontaining proteins (selenoproteins). Incorporation of selenium into the amino acid selenocysteine (Sec), and subsequently into selenoproteins is mediated by Sec tRNA [Ser]Sec .
Although Ca(OH)2 aqueous solution can be effectively used as an absorbent to capture CO2, its performance with highly concentrated CO2 gas mixtures has rarely been reported. Therefore, the present paper investigates the CO2-capture performance of Ca(OH)2 aqueous solution for an about 30% CO2 gas mixture. The Ca(OH)2 concentration in the solution strongly influenced the capture performance of the absorbent. The simultaneous Ca(OH)2 dissolution and CaCO3 production in the absorbent may have substantially hindered the combination of Ca2+ with CO3 2– in suspension. Therefore, a higher Ca(OH)2 concentration in suspension further reduced the CO2 absorption capacity and produced substantially agglomerated CaCO3 with low crystallinity. In contrast, the Ca(OH)2-saturated aqueous solution had the highest absorption rate and capture ratio among the six investigated absorbents. Its calculated absorption capacity of 3.05 g of CO2 [g of Ca(OH)2]−1 L–1 was 3-fold more than that of 1% Ca(OH)2 suspension solution, which confirmed Ca(OH)2-saturated aqueous solution as the most efficient absorbent for CO2 in a Ca(OH)2 aqueous solution system.
The biosynthetic pathway for selenocysteine (Sec), the 21st amino acid in the genetic code whose codeword is UGA, was recently determined in eukaryotes and archaea. Sec tRNA, designated tRNA([Ser]Sec), is initially aminoacylated with serine by seryl-tRNA synthetase and the resulting seryl moiety is converted to phosphoserine by O-phosphoseryl-tRNA kinase to form O-phosphoseryl-tRNA([Ser]Sec). Sec synthase (SecS) then uses O-phosphoseryl-tRNA([Ser]Sec) and the active donor of selenium, selenophosphate, to form Sec-tRNA([Ser]Sec). Selenophosphate is synthesized from selenide and ATP by selenophosphate synthetase 2 (SPS2). Sec was the last protein amino acid in eukaryotes whose biosynthesis had not been established and the only known amino acid in eukaryotes whose biosynthesis occurs on its tRNA. Interestingly, sulfide can replace selenide to form thiophosphate in the SPS2-catalyzed reaction that can then react with O-phosphoseryl-tRNA([Ser]Sec) in the presence of SecS to form cysteine-(Cys-)tRNA([Ser]Sec). This novel pathway of Cys biosynthesis results in Cys being decoded by UGA and replacing Sec in normally selenium-containing proteins (selenoproteins). The selenoprotein, thioredoxin reductase 1 (TR1), was isolated from cells in culture and from mouse liver for analysis of Cys/Sec replacement by MS. The level of Cys/Sec replacement in TR1 was proportional to the level of selenium in the diet of the mice. Elucidation of the biosynthesis of Sec and Sec/Cys replacement provides novel ways of regulating selenoprotein functions and ultimately better understanding of the biological roles of dietary selenium.
Selenium has cancer-preventive activity that is mediated, in part, through selenoproteins. The role of the 15-kDa selenoprotein (Sep15) in colon cancer was assessed by preparing and using mouse colon CT26 cells stably transfected with short hairpin RNA constructs targeting Sep15. Metabolic 75 Se labeling and Northern and Western blot analyses revealed that >90% of Sep15 was downregulated. Growth of the resulting Sep15-deficient CT26 cells was reduced (P < 0.01), and cells formed significantly (P < 0.001) fewer colonies in soft agar compared with control CT26 cells. Whereas most (14 of 15) BALB/c mice injected with control cells developed tumors, few (3 of 30) mice injected with Sep15-deficient cells developed tumors (P < 0.0001). The ability to form pulmonary metastases had similar results. Mice injected with the plasmid-transfected control cells had >250 lung metastases per mouse; however, mice injected with cells with downregulation of Sep15 only had 7.8 ± 5.4 metastases. To investigate molecular targets affected by Sep15 status, gene expression patterns between control and knockdown CT26 cells were compared. Ingenuity Pathways Analysis was used to analyze the 1,045 genes that were significantly (P < 0.001) affected by Sep15 deficiency. The highest-scored biological functions were cancer and cellular growth and proliferation. Consistent with these observations, subsequent analyses revealed a G 2 -M cell cycle arrest in cells with targeted downregulation of Sep15. In contrast to CT26 cells, Sep15-targeted downregulation in Lewis lung carcinoma (LLC1) cells did not affect anchorage-dependent or anchorage-independent cell growth. These data suggest tissue specificity in the cancer-protective effects of Sep15 downregulation, which are mediated, at least in part, by influencing the cell cycle. Cancer Prev Res; 3(5); 630-9. ©2010 AACR.
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