PPAR[gamma]1 phosphorylation enhances proliferation and drug resistance in human fibrosarcoma cells

Post-translational regulation plays a critical role in the control of cell growth and proliferation. The phosphorylation of peroxisome proliferator-activated receptor γ (PPARγ) is the most important post-translational modification. The function of PPARγ phosphorylation has been studied extensively i...

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Bibliographic Details
Published in:Experimental cell research 2014-03, Vol.322 (1), p.30
Main Authors: Pang, Xiaojuan, Shu, Yuxin, Niu, Zhiyuan, Zheng, Wei, Wu, Haochen, Lu, Yan, Shen, Pingping
Format: Article
Language:English
Subjects:
Cell growth
Cellular biology
Cyclin-dependent kinases
Drug resistance
Phosphorylation
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Summary:Post-translational regulation plays a critical role in the control of cell growth and proliferation. The phosphorylation of peroxisome proliferator-activated receptor γ (PPARγ) is the most important post-translational modification. The function of PPARγ phosphorylation has been studied extensively in the past. However, the relationship between phosphorylated PPARγ1 and tumors remains unclear. Here we investigated the role of PPARγ1 phosphorylation in human fibrosarcoma HT1080 cell line. Using the nonphosphorylation (Ser84 to alanine, S84A) and phosphorylation (Ser84 to aspartic acid, S84D) mutant of PPARγ1, the results suggested that phosphorylation attenuated PPARγ1 transcriptional activity. Meanwhile, we demonstrated that phosphorylated PPARγ1 promoted HT1080 cell proliferation and this effect was dependent on the regulation of cell cycle arrest. The mRNA levels of cyclin-dependent kinase inhibitor (CKI) p21Waf1/Cip1 and p27Kip1 descended in PPARγ1S84D stable HT1080 cell, whereas the expression of p18INK4C was not changed. Moreover, compared to the PPARγ1S84A , PPARγ1S84D up-regulated the expression levels of cyclin D1 and cyclin A. Finally, PPARγ1 phosphorylation reduced sensitivity to agonist rosiglitazone and increased resistance to anticancer drug 5-fluorouracil (5-FU) in HT1080 cell. Our findings establish PPARγ1 phosphorylation as a critical event in human fibrosarcoma growth. These findings raise the possibility that chemical compounds that prevent the phosphorylation of PPARγ1 could act as anticancer drugs. [PUBLICATION ABSTRACT]
ISSN:0014-4827
1090-2422
DOI:10.1016/j.yexcr.2014.01.010