DH9, a novel PPARγ agonist suppresses the proliferation of ADPKD epithelial cells: An association with an inhibition of β-catenin signaling.
Autosomal dominant polycystic kidney disease (ADPKD) is a genetic disease that exclusively progresses to renal failure. An important target for the treatment of ADPKD is to reduce cystic cell proliferation. PPARγ agonists such as TZDs are insulin sensitizing agents that have also been reported to decrease tumor growth. Here we tested DH9, a newly synthesized PPARγ agonist on the proliferation of an ADPKD cell line, WT9-12. DH9 showed a potent anti-proliferative activity against ADPKD cells. At high concentration, DH9 also induced apoptotic cell death. The effect of DH9 on cell proliferation was mediated by a PPARγ independent mechanism. Since DH9 decreased the levels of β-catenin in cells via a GSK3β mediated degradation pathway, this acts as a mechanism for growth inhibition by DH9.
Liu
Moyan
M
Nephrology institute of PLA, Department of Internal Medicine, Changzheng Hospital, Second Military Medical University, Shanghai, 200003, People's Republic of China.
Fu
Lili
L
Liu
Chunyan
C
Xiong
Xishan
X
Gao
Xiang
X
Xiao
Min
M
Cai
Houan
H
Hu
Huimin
H
Wang
Xueqi
X
Mei
Changlin
C
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects; D002934:Cinnamates / Q000737:chemistry / Q000494:pharmacology*; D004847:Epithelial Cells / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology*; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D006801:Humans; D007668:Kidney / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D051379:Mice; D047495:PPAR gamma / Q000819:agonists*; D010666:Phenylpropionates / Q000737:chemistry / Q000494:pharmacology*; D016891:Polycystic Kidney, Autosomal Dominant / Q000201:enzymology / Q000378:metabolism / Q000473:pathology*; D011499:Protein Processing, Post-Translational / Q000187:drug effects; D011743:Pyrimidines / Q000737:chemistry / Q000494:pharmacology*; D000077154:Rosiglitazone; D015398:Signal Transduction / Q000187:drug effects*; D045162:Thiazolidinediones / Q000494:pharmacology; D014158:Transcription, Genetic / Q000187:drug effects; D051176:beta Catenin / Q000235:genetics / Q000378:metabolism*
D002934:Cinnamates; D047495:PPAR gamma; D010666:Phenylpropionates; D011743:Pyrimidines; D045162:Thiazolidinediones; D051176:beta Catenin; D000077154:Rosiglitazone; C029010:cinnamic acid; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; C000605507:Gsk3b protein, mouse; D038362:Glycogen Synthase Kinase 3