Thioredoxin inhibits the tumor supressor, PTEN

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DESCRIPTION (provided by applicant): Thioredoxin (Trx) is a small redox protein overexpressed in many human cancers that stimulates cell growth and inhibits programmed cell death (apoptosis). Trx expression is associated with aggressive tumor growth and decreased patient survival. Trx interacts with a variety of proteins, such as the apoptosis signaling kinase (ASK-1), NF-KB, the T7 DNA polymerase and many transcription factors. Nevertheless, the mechanism(s) by which Trx produces its effects are not known. I have identified a novel potential mechanism for Trx?s effects, involving the redox inhibition of the cell survival inhibitor PTEN. PTEN is a lipid phosphatase that antagonizes the effects of phosphatidylinositol-3-kinase in activating Akt, a major pathway inhibiting programmed cell death and promoting cancer cell survival. Reduced but not oxidized Trx inhibits PTEN, indicating that redox activity is necessary for the inhibition, and thioredoxin reductase reverses the inhibition. Docking studies suggested that critical cysteine residues on Trx and on PTEN are necessary for the inhibition of PTEN. Hence, Trx?s effects could be explained, by the binding of Trx directly to PTEN and by its redox inhibition. The objectives of my studies are to further investigate the mechanism of PTEN inhibition by Trx in cancer cells and to examine the biological significance of the interaction between PTEN and Trx in cancer cells.