Selenium deficiency increases the risk of certain cancers and selenium supplementation in deficient locales has demonstrated chemopreventative benefits in several cancers. While developing a model to better understand the relationship between inflammation and cancer, a novel method of inactivation of the tumor suppressor, p53, by electrophilic lipids was elucidated. This mechanism involves the selenoprotein thioredoxin reductase (TrxR) and is selenium dependent. The overall objective of this study is to understand how selenoproteins contribute to cellular processes of transcriptional regulation and cell death by regulating the redox state of the cell. This application tests the hypothesis that TrxR can function as a molecular switch, from contributing reducing equivalents to functioning as a pro-oxidant within the cell upon attack by certain electrophiles. The expectation is that this functional switch has important cellular consequences. It influences the tumor suppressor, p53, as well as redox sensitive processes in protein turnover, and cellular responses to renormalize redox tone. In addition, the 'TrxR-function switch' can promote other cellular processes like cell death. To test these hypotheses, the specific aims are:
Aim 1 : Determine the precise mechanism of p53 inactivation by attenuation of TrxR activity. Is the oxidation state of p53 directly altered by electrophilic lipids or by selenium-compromised TrxR? Furthermore, is a similar mechanism responsible for proteasome pathway inhibition observed by certain electrophilic lipids? Aim 2: Determine roles for TrxR in apoptosis. Is the proposed switch of TrxR function responsible for selenium-compromised TrxR induction of apoptosis and, is fully-functional TrxR necessary for selenium-induced apoptosis? Aim 3: Determine the role that selenoprotein P (SelP) plays in response to lipoxygenase induction and TrxR activity attenuation. Does SelP have a novel function in the regulation of lipid hydroperoxides? These studies provide an integrated framework to understand how electrophiles and selenium/selenoproteins contribute to the etiology of cancer.
