THIOREDOXIN AND THIOREDOXIN REDUCTASE GENE-EXPRESSION IN HUMAN TUMORSAND CELL-LINES, AND THE EFFECTS OF SERUM STIMULATION AND HYPOXIA

Thioredoxin and thioredoxin reductase are redox proteins that have bea t implicated bz the control of cell proliferation and transformation. We report the levels and activity of these proteins and their mRNAs in human primary tumors and tumor cell lines. Half of human primary colo rectal carcinomas (5/10) examined had increased thioredoxin mRNA, of 3 - to over 100-fold, compared to adjacent normal colonic mucosa from th e same subject. Thioredoxin reductase protein and activity were increa sed an average of 2-fold in human colorectal tumors compared to normal mucosa. A number of human hematologic and solid tumor cell lines were studied and showed a 10-fold range of thioredoxin mRNA and a 23-fold range of thioredoxin reductase mRNA. Increased proliferation and hypox ia are factors that might contribute to the increased expression in so lid tumors. We found that serum stimulation of growth arrested MCF-7 b reast cancer cells caused a 59% increase in thioredoxin mRNA and a 62% increase in thioredoxin reductase mRNA by 24 hours. Exposure of HT-29 colon cancer cells to hypoxia resulted in a 14-fold increase in thior edoxin mRNA by 16 hours, and a transient 4-fold increase in thioredoxi n reductase mRNA at 1 hour that had returned to control levels by 8 ho urs. Cancer cells were found to release thioredoxin into the medium at rates between 1 to 2 pmole/10(6) cells/3 hours. The rate of secretion was not, however, related to cellular-levels of thioredoxin. The resu lts of the study show that the expression of thioredoxin and thioredox in reductase are increased several fold in some human solid tumors com pared to normal tissue. Secretion of thioredoxin, which is known to ha ve a direct growth stimulating activity, by human tumor cells might le ad to the stimulation of cancer cell growth.