PPARγ1 phosphorylation enhances proliferation and drug resistance in human fibrosarcoma cells

Journal Article · Mon Mar 10 00:00:00 EDT 2014 · Experimental Cell Research

DOI:https://doi.org/10.1016/J.YEXCR.2014.01.010· OSTI ID:22395870

Pang, Xiaojuan; Shu, Yuxin; Niu, Zhiyuan; Zheng, Wei; Wu, Haochen ^[1]; Lu, Yan ^[1]; Shen, Pingping ^[1]

---

1. State Key Laboratory of Pharmaceutical Biotechnology, Nanjing University, Nanjing (China)

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{sup Waf1/Cip1} and p27{sup Kip1} descended in PPARγ1{sup S84D} stable HT1080 cell, whereas the expression of p18{sup INK4C} was not changed. Moreover, compared to the PPARγ1{sup S84A}, PPARγ1{sup 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. - Highlights: • Phosphorylation attenuates PPARγ1 transcriptional activity. • Phosphorylated PPARγ1 promotes HT1080 cells proliferation. • PPARγ1 phosphorylation regulates cell cycle by mediating expression of cell cycle regulators. • PPARγ1 phosphorylation reduces sensitivity to agonist and anticancer drug. • Our findings establish PPARγ1 phosphorylation as a critical event in HT1080 cells growth.

• OSTI ID: 22395870
• Journal Information: Experimental Cell Research, Vol. 322, Issue 1; Other Information: Copyright (c) 2014 Elsevier Science B.V., Amsterdam, The Netherlands, All rights reserved.; Country of input: International Atomic Energy Agency (IAEA); ISSN 0014-4827
• Country of Publication: United States
• Language: English

Related Subjects

60 APPLIED LIFE SCIENCES
ALANINES
ANTIGENS
ANTINEOPLASTIC DRUGS
ASPARTIC ACID
BROMIDES
CELL CYCLE
CELL PROLIFERATION
COMPARATIVE EVALUATIONS
FLUORESCENCE
HUMAN POPULATIONS
IODIDES
MESSENGER-RNA
MODIFICATIONS
MONOCLINIC LATTICES
MUTANTS
NEOPLASMS
PHOSPHORYLATION
PLANT GROWTH
PROLIFERATION
RECEPTORS
REGULATIONS
URACILS