Peroxisome proliferator-activated receptor gamma agonists induce proteasome-dependent degradation of cyclin D1 and estrogen receptor alpha in MCF-7 breast cancer cells.
Treatment of MCF-7 cells with the peroxisome proliferator-activated receptor (PPAR) gamma agonists ciglitazone or 15-deoxy-Delta 12,14-prostaglandin J2 resulted in a concentration- and time-dependent decrease of cyclin D1 and estrogen receptor (ER) alpha proteins, and this was accompanied by decreased cell proliferation and G(1)-G(0)-->S-phase progression. Down-regulation of cyclin D1 and ER alpha by PPARgamma 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-deoxy-Delta 12,14-prostaglandin J2 and immunoprecipitation with cyclin D1 or ER alpha antibodies, there was enhanced formation of ubiquitinated cyclin D1 and ER alpha bands. Thus, PPARgamma-induced inhibition of breast cancer cell growth is due, in part, to proteasome-dependent degradation of cyclin D1 (and ER alpha), and this pathway may be important for other cancer cell lines.
Qin
Chunhua
C
Department of Veterinary Physiology and Pharmacology, Texas A&M University, College Station, Texas 77843, USA.
Burghardt
Robert
R
Smith
Roger
R
Wormke
Mark
M
Stewart
Jessica
J
Safe
Stephen
S
D001943:Breast Neoplasms / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D002455:Cell Division / Q000187:drug effects; D019938:Cyclin D1 / Q000235:genetics / Q000378:metabolism*; D003546:Cysteine Endopeptidases / Q000378:metabolism*; D015536:Down-Regulation / Q000187:drug effects; D047628:Estrogen Receptor alpha; D016193:G1 Phase / Q000187:drug effects; D006801:Humans; D009097:Multienzyme Complexes / Q000378:metabolism*; D015230:Prostaglandin D2 / Q000031:analogs & derivatives* / Q000494:pharmacology*; D046988:Proteasome Endopeptidase Complex; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D018160:Receptors, Cytoplasmic and Nuclear / Q000819:agonists*; D011960:Receptors, Estrogen / Q000378:metabolism*; D016196:S Phase / Q000187:drug effects; D013844:Thiazoles / Q000494:pharmacology*; D045162:Thiazolidinediones; D014157:Transcription Factors / Q000819:agonists*; D014158:Transcription, Genetic / Q000187:drug effects; D014407:Tumor Cells, Cultured; D025801:Ubiquitin / Q000378:metabolism
D047628:Estrogen Receptor alpha; D009097:Multienzyme Complexes; D012333:RNA, Messenger; D018160:Receptors, Cytoplasmic and Nuclear; D011960:Receptors, Estrogen; D013844:Thiazoles; D045162:Thiazolidinediones; D014157:Transcription Factors; D025801:Ubiquitin; D019938:Cyclin D1; C037112:9-deoxy-delta-9-prostaglandin D2; D003546:Cysteine Endopeptidases; D046988:Proteasome Endopeptidase Complex; D015230:Prostaglandin D2; C039671:ciglitazone