Thioredoxin is a small redox protein that undergoes NADPH-dependent reduction by the flavoprotein thioredoxin reductase. Thioredoxin provides reducing equivalents to ribonucleotide reductase, the first unique step of DNA synthesis, and through thiol-disulfide exchange regulates the activity of a number of transcription factors. Redox activity is essential for the biological activity of thioredoxin. Our work provides strong evidence that the gene for thioredoxin is a new human oncogene. We have shown that transfection of mouse NIH 3T3 normal embryonic cells with human thioredoxin causes their transformation. Transfection of mouse thymoma cells with thioredoxin inhibits spontaneous and drug induced apoptosis in vitro and in vivo, and causes aggressive tumor growth in vivo. Transfection of human cancer cells with thioredoxin increases their anchorage independent growth and stimulates tumor growth in vivo. In contrast, transfection with a dominant-negative redox-inactive thioredoxin inhibits anchorage-independent growth and completely prevents tumor formation by the cells in vivo. We have shown that half of the human primary lung, colon, and gastric cancers over-express thioredoxin compared to normal tissue. In human primary gastric carcinomas, thioredoxin over- expression is highly correlated with increased cell proliferation and decreased apoptosis. Thus, the hypothesis on which our studies are based is that thioredoxin is a critical regulator of the growth and transformed phenotype of some human cancers and that over-expression of thioredoxin may be a cause of human cancer. We also propose that thioredoxin offers a rational and feasible target for the development of new drugs for the treatment of cancer. There remain important unanswered questions concerning the role thioredoxin plays in human cancer, its mechanism of action, its ability to determine response to therapy and the action of drugs that inhibit thioredoxin. These questions will be addressed by our proposed studies.
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