Thioredoxin reductase as a novel molecular target for cancer therapy

Nguyen, Phuongmai; Awwad, Rania T.; Smart, Dee Dee; Spitz, Douglas R.; Gius, David

doi:10.1016/j.canlet.2005.04.028

Cited by 153 publications

(114 citation statements)

References 68 publications

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“…Thioredoxin reductase (TR) is important for maintaining the reduced form of TRX1 in cells, and the inhibition of TR prevents the conversion of oxidized TRX1 into reduced form [30,31]. We found that As 2 O 3 could inhibit TR activity (data not shown), which is consistent with a previous report [32].…”

Section: 4-dinitrochlorobenzene (Dncb) Elicits the Oxidization Of Tsupporting

confidence: 92%

Redox status of thioredoxin-1 (TRX1) determines the sensitivity of human liver carcinoma cells (HepG2) to arsenic trioxide-induced cell death

et al. 2007

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Intracellular redox homeostasis plays a critical role in determining tumor cells' sensitivity to drug-induced apoptosis. Here we investigated the role of thioredoxin-1 (TRX1), a key component of redox regulation, in arsenic trioxide (As 2 O 3 )-induced apoptosis. Over-expression of wild-type TRX1 in HepG 2 cells led to the inhibition of As 2 O 3 -induced cytochrome c (cyto c) release, caspase activation and apoptosis, and down-regulation of TRX1 expression by RNAi sensitized HepG 2 cells to As 2 O 3 -induced apoptosis. Interestingly, mutation of the active site of TRX1 from Cys 32/35 to Ser 32/35 converted this molecule from an apoptotic protector to an apoptotic promoter. In an effort to understand the mechanisms of this conversion, we used isolated mitochondria from mouse liver and found that recombinant wild-type TRX1 could protect mitochondria from the apoptotic changes. In contrast, the mutant form of TRX1 alone elicited mitochondria-related apoptotic changes, including the mitochondrial permeability transition pore (mPTP) opening, loss of mitochondrial membrane potential, and cyto c release from mitochondria. These apoptotic effects were inhibited by cyclosporine A (CsA), indicating that mutant TRX1 targeted to mPTP. Alteration of TRX1 from its reduced form to oxidized form in vivo by 2,4-dinitrochlorobenzene (DNCB), a specific inhibitor of TRX reductase, also sensitized HepG 2 cells to As 2 O 3 -induced apoptosis. These data suggest that TRX1 plays a central role in regulating apoptosis by blocking cyto c release, and inactivation of TRX1 by either mutation or oxidization of the active site cysteines may sensitize tumor cells to As 2 O 3 -induced apoptosis.

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Section: 4-dinitrochlorobenzene (Dncb) Elicits the Oxidization Of Tsupporting

confidence: 92%

Redox status of thioredoxin-1 (TRX1) determines the sensitivity of human liver carcinoma cells (HepG2) to arsenic trioxide-induced cell death

et al. 2007

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“…Selenium is known as a trace element with potent cancer prevention function (19,20). On the other hand, since overexpression of TR1 is consistently observed in many tumors and several antitumor drugs are known inhibitors of TR1 (29 -31), this selenoenzyme was proposed as a target for tumor therapy (7,9,10,15,32). In addition, selenium deficiency has been reported to decrease tumor incidence in some cancer models in animals (33).…”

Section: Discussionmentioning

confidence: 99%

“…see Refs. [7][8][9][10]. A variety of potent TR1 inhibitors have been shown to alter the cancer-related properties of tumors and numerous malignant cells (see Refs.…”

mentioning

confidence: 99%

Thioredoxin Reductase 1 Deficiency Reverses Tumor Phenotype and Tumorigenicity of Lung Carcinoma Cells

Yoo

Carlson

et al. 2006

Journal of Biological Chemistry

244

191

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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...

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“…L-Buthionine sulfoximine (BSO) is an example of an inhibitor of cellular GSH synthesis that has been studied in combination with ionizing radiation [49], and is currently in phase II clinical trials in combination with melphalan. Another potential strategy for disrupting the antioxidant response of the cell is by targeting thioredoxin reductase, a component of several redox-regulated pathways [50].…”

Section: Cancer and Redox State Modulationmentioning

confidence: 99%

Harnessing drug resistance: Using ABC transporter proteins to target cancer cells

Leitner

Kachadourian

Day

2007

Biochemical Pharmacology

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The ATP-binding cassette (ABC) class of proteins is one of the most functionally diverse transporter families found in biological systems. Although the abundance of ABC proteins varies between species, they are highly conserved in sequence and often demonstrate similar functions across prokaryotic and eukaryotic organisms. Beginning with a brief summary of the events leading to our present day knowledge of ABC transporters, the purpose of this review is to discuss the potential for utilizing ABC transporters as a means for cellular glutathione (GSH) modulation. GSH is one of the most abundant thiol antioxidants in cells. It is involved in cellular division, protein and DNA synthesis, maintenance of cellular redox status and xenobiotic metabolism. Cellular GSH levels are often altered in many disease states including cancer. Over the past two decades there has been considerable emphasis on methods to sensitize cancer cells to chemotherapeutics and ionization radiation therapy by GSH depletion. We contend that ABC transporters, particularly multi-drug resistant proteins (MRPs), may be used as therapeutic targets for applications aimed at modulation of GSH levels. This review will emphasize MRP-mediated modulation of intracellular GSH levels as a potential alternative and adjunctive approach for cancer therapy.

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Thioredoxin reductase as a novel molecular target for cancer therapy

Cited by 153 publications

References 68 publications

Redox status of thioredoxin-1 (TRX1) determines the sensitivity of human liver carcinoma cells (HepG2) to arsenic trioxide-induced cell death

Redox status of thioredoxin-1 (TRX1) determines the sensitivity of human liver carcinoma cells (HepG2) to arsenic trioxide-induced cell death

Thioredoxin Reductase 1 Deficiency Reverses Tumor Phenotype and Tumorigenicity of Lung Carcinoma Cells

Harnessing drug resistance: Using ABC transporter proteins to target cancer cells

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