Protein disulfide isomerase is a multifunctional regulator of estrogenic status in target cells

Earlier studies showed that protein disulfide isomerase (PDI), a well-known protein folding catalyst and a molecular chaperone, can bind estrogens and may also directly interact with the estrogen receptor (ER). In this study, we sought to determine the biological functions of these intriguing properties of PDI. We showed that PDI can function as a high-capacity intracellular 17β-estradiol (E2)-binding protein that increases the concentration and accumulation of E2 in live cells. The intracellular PDI-bound E2 can be released from PDI upon a drop in E2 levels and the released E2 can augment estrogen receptor-mediated transcriptional activity and mitogenic actions in cultured cells. In addition, the binding of E2 by PDI also reduces the rate of metabolic disposition of this hormone. We showed, for the first time, that knockdown of PDI in MCF-7 human breast cancer cells with RNA interference down-regulates ERα protein but up-regulates ERβ protein, resulting in a drastic increase in ERβ/ERα ratio, which is a crucial determinant of different cellular responses to estrogens. To explain the mechanism of this differential regulation, we also studied the interactions of PDI with ERα and ERβ. We found that PDI can directly interact with ERα, but it does not interact with ERβ. Altogether, these data showed that PDI is a multifunctional regulator of intracellular estrogenic status. It not only regulates the intracellular concentrations of E2 and the magnitude of estrogen action, but it also modulates the ERβ/ERα ratio.