PPARgamma agonists attenuate proliferation and modulate Wnt/beta-catenin signalling in melanoma cells.
Peroxisome proliferator-activated receptor-gamma (PPARgamma) is a member of the nuclear hormone receptor (NHR) superfamily of ligand-activated transcriptional regulators. Accumulating evidence suggests that PPARgamma agonists such as the thiazolidinediones (TZDs) may prove to be useful anti-cancer agents exhibiting anti-proliferative and/or pro-apoptotic affects in a range of cancer cell types including melanoma, however, the mechanisms underlying this effect remain unclear. We have demonstrated the anti-proliferative effects of full and partial PPARgamma modulators in human melanoma cell lines. Ablation of PPARgamma expression in the MM96L melanoma cell line by siRNA mediated mechanisms attenuates the anti-proliferative effect of these agents suggesting this effect is directly mediated by PPARgamma. The mechanisms underlying the anti-proliferative effects of PPARgamma in melanoma cells involve the regulation of expression of a number of critical cell cycle genes and beta-catenin. Moreover, our data indicate that PPARgamma modulates Wnt/beta-catenin mediated signalling in melanoma cells in an agonist dependent manner.
Smith
Aaron G
AG
The University of Queensland, Institute for Molecular Bioscience, Qld 4072, Australia. a.smith@imb.uq.edu.au
Beaumont
Kimberley A
KA
Smit
Darren J
DJ
Thurber
Amy E
AE
Cook
Anthony L
AL
Boyle
Glen M
GM
Parsons
Peter G
PG
Sturm
Richard A
RA
Muscat
George E O
GE
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D019556:COS Cells; D002453:Cell Cycle / Q000187:drug effects / Q000235:genetics; D048708:Cell Growth Processes / Q000187:drug effects / Q000502:physiology; D045744:Cell Line, Tumor; D002522:Chlorocebus aethiops; D002839:Chromans / Q000494:pharmacology; D006218:Halofenate / Q000494:pharmacology; D006801:Humans; D008545:Melanoma / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D047495:PPAR gamma / Q000819:agonists* / Q000096:biosynthesis / Q000235:genetics; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D034741:RNA, Small Interfering / Q000235:genetics; D000077154:Rosiglitazone; D015398:Signal Transduction / Q000187:drug effects; D045162:Thiazolidinediones / Q000494:pharmacology; D000077288:Troglitazone; D051153:Wnt Proteins / Q000819:agonists* / Q000235:genetics / Q000378:metabolism*; D051176:beta Catenin / Q000235:genetics / Q000378:metabolism*
D000970:Antineoplastic Agents; D002839:Chromans; D047495:PPAR gamma; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D045162:Thiazolidinediones; D051153:Wnt Proteins; D051176:beta Catenin; D000077154:Rosiglitazone; D000077288:Troglitazone; D006218:Halofenate