Orphan Receptor TR3/nur77 and Apoptosis in Prostate Cancer Cells

摘要

TR3 (also called Nur77 or NGFI-B), an immediate-early response gene and an orphan member of the nuclear receptor superfamily, regulates both survival and death of prostate cancer cells. It is overexpressed in prostate tumor and acts in the nucleus to promote tumor cell growth. In response to certain apoptotic stimuli, TR3 migrates from the nucleus to the cytoplasm where it targets mitochondria to induce cytochrome C release and apoptosis. Translocation of TR3 from the nucleus to the cytoplasm requires its heterodimerization with retinoid X receptor (RXR) and it is highly regulated by RXR ligands. In addition, phosphorylation of TR3 protein modulates its subcellular localization and biological activities. Mitochondrial localization of TR3 is mediated by its interaction with Bcl-2, a potent anti-apoptotic protein that is overexpressed in prostate tumors. Binding of TR3 to Bcl-2 induces a Bcl-2 conformational change, resulting in conversion of Bcl-2 from a protector to killer. These results establish a novel TR3-dependent apoptotic pathway in prostate cancer cells and its regulation. They also demonstrate that TR3 is an attractive molecular target for developing new prostate cancer therapeutics.