Peroxisome Proliferator-activated Receptor Agonists Induce Proteasome-dependent Degradation of Cyclin D1 and Estrogen Receptor in MCF-7 Breast Cancer Cells

Treatment of MCF-7 cells with the peroxisome proliferator-activated receptor (PPAR) agonists ciglitazone or 15-deoxy12,14-prostaglandin J2 resulted in a concentrationand time-dependent decrease of cyclin D1 and estrogen receptor (ER) proteins, and this was accompanied by decreased cell proliferation and G1-G03S-phase progression. Downregulation of cyclin D1 and ER by PPAR agonists was inhibited in cells cotreated with the proteasome inhibitors MG132 and PSII, but not in cells cotreated with the protease inhibitors calpain II and calpeptin. Moreover, after treatment of MCF-7 cells with 15-deoxy12,14-prostaglandin J2 and immunoprecipitation with cyclin D1 or ER antibodies, there was enhanced formation of ubiquitinated cyclin D1 and ER bands. Thus, PPAR -induced inhibition of breast cancer cell growth is due, in part, to proteasome-dependent degradation of cyclin D1 (and ER ), and this pathway may be important for other cancer cell lines.