Fenofibrate antagonizes Chk2 activation by inducing Wip1 expression: implications for cell proliferation and tumorigenesis.
OBJECTIVE
Fenofibrate is a peroxisome proliferator-activated receptor alpha (PPARalpha) agonist that has been widely used to treat dyslipidemia. Previous studies have suggested that fenofibrate plays a role in cell proliferation and the development of hepatocarcinoma, but the underlying mechanism has not been fully characterized. In this report, we investigated whether fenofibrate treatment affected on the machinery of cell cycle checkpoint using nocodazole-induced cell cycle arrest.


METHODS
The human normal liver cell line, CCL13 cells were treated with nocodazole and fenofibrate. Flow cytometry was performed for cell cycle analysis, and checkpoint kinase 2 (Chk2) and phosphatase Wip1 were analyzed by Western blot.


RESULTS
Fenofibrate treatment overrode nocodazole-induced G2/M cell cycle arrest in a PPARalpha-independent manner. Mechanistically, fenofibrate treatment inhibited phosphorylation of checkpoint kinase Chk2 induced by nocodazole, and increased the expression of Wip1, a negative regulator of Chk2, suggesting that fenofibrate suppressed the nocodazole-induced G2/M cell cycle checkpoint through Wip1-mediated inhibition of Chk2 activation.


CONCLUSIONS
These results reveal a novel role of fenofibrate in cell cycle checkpoint control and provide a possible mechanistic explanation for how fenofibrate promotes cell proliferation and carcinogenesis.
Joe
Yeonsoo
Y
Department of Pharmacology, Medical Sciences Research Center, Dong-A University College of Medicine, Busan, South Korea.
Do
Mi-Hyang
MH
Seo
Eunhui
E
Kang
Soojeong
S
Park
Hwan-Tae
HT
Yun
Jeanho
J
Lee
Hye-Jeong
HJ
D015153:Blotting, Western; D002455:Cell Division / Q000187:drug effects; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects*; D064447:Checkpoint Kinase 2; D011345:Fenofibrate / Q000494:pharmacology*; D005434:Flow Cytometry; D016195:G2 Phase / Q000187:drug effects; D006801:Humans; D000960:Hypolipidemic Agents / Q000494:pharmacology*; D015739:Nocodazole / Q000494:pharmacology; D047493:PPAR alpha / Q000819:agonists; D010749:Phosphoprotein Phosphatases / Q000235:genetics* / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D000071636:Protein Phosphatase 2C; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors*
D000960:Hypolipidemic Agents; D047493:PPAR alpha; D064447:Checkpoint Kinase 2; C578634:CHEK2 protein, human; D017346:Protein Serine-Threonine Kinases; C000607458:PPM1D protein, human; D010749:Phosphoprotein Phosphatases; D000071636:Protein Phosphatase 2C; D015739:Nocodazole; D011345:Fenofibrate