PPARγ1 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 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) p21(Waf1/Cip1) and p27(Kip1) descended in PPARγ1(S84D) stable HT1080 cell, whereas the expression of p18(INK4C) was not changed. Moreover, compared to the PPARγ1(S84A), PPARγ1(S84D) 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.
State Key Laboratory of Pharmaceutical Biotechnology, Nanjing University, Nanjing, China.
Xiaojuan
X
Pang
State Key Laboratory of Pharmaceutical Biotechnology, Nanjing University, Nanjing, China.
Yuxin
Y
Shu
State Key Laboratory of Pharmaceutical Biotechnology, Nanjing University, Nanjing, China.
Zhiyuan
Z
Niu
State Key Laboratory of Pharmaceutical Biotechnology, Nanjing University, Nanjing, China.
Wei
W
Zheng
State Key Laboratory of Pharmaceutical Biotechnology, Nanjing University, Nanjing, China.
Haochen
H
Wu
State Key Laboratory of Pharmaceutical Biotechnology, Nanjing University, Nanjing, China. Electronic address: luyan@nju.edu.cn.
Yan
Y
Lu
State Key Laboratory of Pharmaceutical Biotechnology, Nanjing University, Nanjing, China; Model Animal Research Center (MARC), Nanjing University, Nanjing, China. Electronic address: ppshen@nju.edu.cn.
Pingping
P
Shen
D045744:Cell Line, Tumor; D049109:Cell Proliferation; D019008:Drug Resistance, Neoplasm; D005354:Fibrosarcoma / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D015972:Gene Expression Regulation, Neoplastic; D018816:Genes, cdc; D057809:HEK293 Cells; D006801:Humans; D047495:PPAR gamma / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation; D011494:Protein Kinases / Q000378:metabolism*; D011499:Protein Processing, Post-Translational; D015533:Transcriptional Activation
D047495:PPAR gamma; D011494:Protein Kinases
Cell cycle; Cell proliferation; Drug resistance; PPARγ1 phosphorylation