Orphan Receptor TR3/nur77 and Apoptosis in Prostate Cancer Cells

摘要

A class of new synthetic retinoids related to 6-3-(L-ADAMANTYL)-4- HYDROXYPHENYL-2- naphthalene carboxylic acid (AHPN/CD437) effectively induce apoptosis of prostate cancer cells. Our previous study demonstrated that AHPN/ CD437-induced apoptosis of LNCaP prostate cancer cells requires the expression of TR3 (also called nur77 or NGFI-B) that is an orphan member of the steroid/ thyroid/retinoid receptor superfamily and its nuclear export and mitochondrial localization. In studying how TR3 nuclear export, mitochondrial targeting and apoptosis induction in prostate cancer cells are regulated, we have demonstrated that the migration of TR3 from the nucleus to the cytoplasm requires retinoid X receptor (RXR) through their heterodimerization. In addition, we show that the T3 cytoplasmic localization and apoptotic effect are inhibited by RXR ligand 9- cis retinoic acid. Moreover, we demonstrate that TR3 interacts with Bcl-2 and that the interaction is essential for TR3 to target mitochondria and to induce apoptosis. These data not only enhance our understanding the molecular mechanism by which TR3 nuclear export, mitochondrial targeting and apoptosis induction are regulated but also provide important information for developing novel strategies for inducing apoptosis of prostate cancer cells.