title: Activation of peroxisome proliferator-activated receptor delta stimulates the proliferation of human breast and prostate cancer cell lines.
abstract: The nuclear receptor peroxisome proliferator-activated receptor delta [PPARdelta/beta (NR1C2)] has been implicated in colorectal carcinogenesis by various molecular genetic observations. These observations have recently been supported by studies of activation of PPARdelta by pharmacological agents. Here we present the first report of the stimulation of breast and prostate cancer cell growth using PPARdelta selective agonists. Activation of PPARdelta with compound F stimulated proliferation in breast (T47D, MCF7) and prostate (LNCaP, PNT1A) cell lines, which are responsive to sex hormones. Conversely, we have found that several steroid-independent cell lines, including colon lines, were unresponsive to compound F. These findings were confirmed with an additional high-affinity PPARdelta agonist, GW501516. Conditional expression of PPARdelta in MCF7 Tet-On cells resulted in a doxycycline-enhanced response to GW501516, thus providing direct genetic evidence for the role of PPARdelta in the proliferative response to this drug. Activation of PPARdelta in T47D cells resulted in increased expression of the proliferation marker Cdk2 and also vascular endothelial growth factor alpha (VEGFalpha) and its receptor, FLT-1, thus, suggesting that PPARdelta may initiate an autocrine loop for cellular proliferation and possibly angiogenesis. Consistent with this hypothesis, we demonstrated a pro-proliferative effect of GW501516 on human umbilical vein endothelial cell cultures and found that GW501516 also regulated the expression of VEGFalpha and FLT-1 in these cells. Our observations provide the first evidence that activation of PPARdelta can result in increased growth in breast and prostate cancer cell lines and primary endothelial cells and supports the possibility that PPARdelta antagonists may be of therapeutic value in the treatment of breast and prostate cancer.
authors.affiliation: Biomedical Research Centre and Cancer Research United Kingdom Molecular Pharmacology Unit, Ninewells Hospital and Medical School, University of Dundee, Dundee, Scotland, United Kingdom.
authors.forename: Ruth L
authors.initials: RL
authors.lastname: Stephen
authors.forename: Mattias C U
authors.initials: MC
authors.lastname: Gustafsson
authors.forename: Morag
authors.initials: M
authors.lastname: Jarvis
authors.forename: Roger
authors.initials: R
authors.lastname: Tatoud
authors.forename: Barry R
authors.initials: BR
authors.lastname: Marshall
authors.forename: Deborah
authors.initials: D
authors.lastname: Knight
authors.forename: Ewa
authors.initials: E
authors.lastname: Ehrenborg
authors.forename: Adrian L
authors.initials: AL
authors.lastname: Harris
authors.forename: C Roland
authors.initials: CR
authors.lastname: Wolf
authors.forename: Colin N A
authors.initials: CN
authors.lastname: Palmer
mesh_terms: D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D002455:Cell Division / Q000187:drug effects / Q000235:genetics / Q000502:physiology; D045744:Cell Line, Tumor; D003110:Colonic Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D005260:Female; D015870:Gene Expression / Q000187:drug effects; D017930:Genes, Reporter / Q000187:drug effects / Q000235:genetics; D018816:Genes, cdc / Q000187:drug effects; D006801:Humans; D008024:Ligands; D008156:Luciferases / Q000096:biosynthesis / Q000235:genetics; D008297:Male; D009376:Neoplasms, Hormone-Dependent / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D011471:Prostatic Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D018160:Receptors, Cytoplasmic and Nuclear / Q000819:agonists* / Q000096:biosynthesis / Q000235:genetics; D011960:Receptors, Estrogen / Q000096:biosynthesis / Q000235:genetics; D020218:Response Elements / Q000187:drug effects; D015398:Signal Transduction / Q000187:drug effects; D013844:Thiazoles / Q000494:pharmacology; D014157:Transcription Factors / Q000819:agonists* / Q000096:biosynthesis / Q000235:genetics; D015533:Transcriptional Activation / Q000187:drug effects
chemical_list: C425931:GW 501516; D008024:Ligands; D012333:RNA, Messenger; D018160:Receptors, Cytoplasmic and Nuclear; D011960:Receptors, Estrogen; D013844:Thiazoles; D014157:Transcription Factors; D008156:Luciferases