Thioredoxin reductase as a novel molecular target for cancer therapy

doi:10.1016/j.canlet.2005.04.028

Cancer Letters

Volume 236, Issue 2, 18 May 2006, Pages 164-174

https://doi.org/10.1016/j.canlet.2005.04.028 Get rights and content

Abstract

Tumor cell proliferation, de-differentiation, and progression depend on a complex combination of altered cell cycle regulation, excessive growth factor pathway activation, and decreased apoptosis. The understanding of these complex mechanisms should lead to the identification of potential targets for therapeutic intervention. Redox-sensitive signaling factors also regulate multiple cellular processes including proliferation, cell cycle, and pro-survival signaling cascades, suggesting their potential as molecular targets for anticancer agents. These observations suggest that redox-sensitive signaling factors may be potential novel molecular markers.

We hypothesized that thioredoxin reductase-1 (TR), a component of several redox-regulated pathways, may represent a potential molecular target candidate in response to agents that induce oxidative stress. There have been numerous biological studies over the last decade investigating the cell biological, biochemical, and genetic properties of TR both in culture and in in vivo models. In addition, using a series of permanent cell lines that express either a wild-type TR or a dominant mutant TR gene or a chemical agent that inhibits TR we demonstrated that TR meets most criteria that would identify a molecular target. Based on these results we believe TR is a potential molecular target and discuss potential clinical possibilities.

Section snippets

Pro-survival signaling factors as molecular targets

Eukaryotic, and more importantly tumor cells, evolve adaptive responses to multiple forms of environmental stress by initiating genetically preprogrammed signaling pathways [1], [2]. These adaptive responses include the activation of cellular machinery involved in DNA repair, cell cycle arrest, apoptosis, gene induction, and pro-proliferative/survival [3], [4]. The potential relationship of intracellular pro-survival factors, observed with malignant progression, is critical to predicting how

Oxidative stress

It has long been appreciated that actively dividing and metabolically hyperactive cells produce free radicals and reactive oxygen species (ROS) that are involved in a number of intracellular processes. These include oxygen metabolism, immune-mediated attack of pathogens, inflammation, signal transduction/gene expression pathways, and a number of human diseases [14], [15], [16], [17]. In the presence of O₂, free radicals give rise to ROS including hydrogen peroxide (H₂O₂) and organic

Redox and thioredoxin reductase

Tumor cells primarily derive energy via altered glucose utilization from increasing glycolysis and pentose phosphate cycle activity resulting in the loss of regulation between glycolytic metabolism and respiration [32], [33], [34], [35]. It has been suggested that tumor cells increase glycolytic metabolism resulting from the excess ROS production due to the accelerated cell processes required to support division. When a cell ‘senses’ oxidative stress it can respond by decreasing ROS production,

TR as a molecular target

The use of modern technologies and high throughput screening allows the identification of agents that can inhibit specific intracellular factors/proteins that may be fundamental to tumor cell proliferation and growth. These signaling cascades are frequently activated or distorted by mutations in cancer cells, thus presenting the possibility that they may be potential molecular targets for new therapeutic agents. As such, identifying potential molecular targets to be used in high throughput drug

Other redox signaling factors as molecular targets

It also seems logical to determine if other redox-sensitive signaling factors downstream of TR would also meet parts of the criteria designed to identify potential molecular targets. Since, TRX is a major target of redox regulation by TR, it would be reasonable to examine if it would also be a potential anticancer target. In this regard, groups have recently reported that TR and other related redox-sensitive signaling factors are increased in tumors versus normal cells or found in higher levels

Conclusions

Oxidative stress has been suggested to play a role in various clinical diseases, including neurodegenerative disorders, endocrine abnormalities, and cancer. While the understanding of the specific signals that are sensitive to changes in the cellular oxidation/reduction status of the cell is rapidly expanding, the specific mechanism(s) and molecules that bridge the gap between cellular kinases, phosphatases and small redox-sensitive molecules remains unclear. However, it appears that many types

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Mini-reviewThioredoxin reductase as a novel molecular target for cancer therapy

Abstract

Section snippets

Pro-survival signaling factors as molecular targets

Oxidative stress

Redox and thioredoxin reductase

TR as a molecular target

Other redox signaling factors as molecular targets

Conclusions

Methods Enzymol.

Cell

J. Biol. Chem.

Radiother. Oncol.

Toxicol. Lett.

Cell

Trends Genet.

Methods Enzymol.

Free Radic. Biol. Med.

J. Biol. Chem.

Toxicol. Lett.

Free Radic. Biol. Med.

Life Sci.

Free Radic. Biol. Med.

Free Radic. Biol. Med.

Biochem. Pharmacol.

Chem. Biol. Interact.

Biochem. Biophys. Res. Commun.

Biochem. Biophys. Res. Commun.

Curr. Opin. Cell Biol.

J. Biol. Chem.

Int. J. Radiat. Oncol. Biol. Phys.

Trends Biochem. Sci.

J. Biol. Chem.

Arch. Biochem. Biophys.

Biochem. Biophys. Res. Commun.

J. Lab. Clin. Med.

Am. J. Pathol.

Pharmacol. Ther.

Int. J. Radiat. Oncol. Biol. Phys.

J. Biol. Chem.

Bioorg. Med. Chem. Lett.

J. Biol. Chem.

Cell

Fos is phosphorylated by p34cdc2, cAMP-dependent protein kinase and protein kinase C at multiple sites clustered within regulatory regions

Oncogene

Zen and the art of Fos and Jun

Nature

Transcriptional activation and repression by Fos are independent functions: the C terminus represses immediate-early gene expression via CArG elements

Mol. Cell. Biol.

Glucose deprivation-induced oxidative stress in human tumor cells: a fundamental defect in metabolism?

Ann. NY Acad. Sci.

Geldanamycin and 17-allylamino-17-demethoxygeldanamycin potentiate the in vitro and in vivo radiation response of cervical tumor cells via the heat shock protein 90-mediated intracellular signaling and cytotoxicity

Cancer Res.

Thioredoxin reductase as a potential molecular target for anticancer agents that induce oxidative stress

Cancer Res.

Contribution of increased glutathione content to mechanisms of oxidative stress resistance in hydrogen peroxide resistant hamster fibroblasts

J. Cell. Physiol.

Transcriptional regulation by Fos and Jun in vitro: interaction among multiple activator and regulatory domains

Mol. Cell. Biol.

Involvement of reactive oxygen intermediates in the induction of c-jun gene transcription by ionizing radiation

Biochemistry

Heat-induced cytotoxicity in H2O2-resistant Chinese hamster fibroblasts

J. Cell. Physiol.

X-irradiation, phorbol esters, and H2O2 stimulate mitogen-activated protein kinase activity in NIH3T3 cells through the formation of reactive oxygen intermediates

Cancer Res.

Mini-review
Thioredoxin reductase as a novel molecular target for cancer therapy

Heat-induced cytotoxicity in H₂O₂-resistant Chinese hamster fibroblasts

X-irradiation, phorbol esters, and H₂O₂ stimulate mitogen-activated protein kinase activity in NIH3T3 cells through the formation of reactive oxygen intermediates