title: Rosiglitazone sensitizes hepatocellular carcinoma cell lines to 5-fluorouracil antitumor activity through activation of the PPARgamma signaling pathway.
abstract: OBJECTIVE
  Resistance to 5-fluorouracil (5-FU) is a major cause of chemotherapy failure in advanced hepatocellular carcinoma (HCC). Rosiglitazone, a peroxisome proliferator-activated receptor gamma (PPARgamma) agonist, has a crucial role in growth inhibition and induction of apoptosis in several carcinoma cell lines. In this study, we examine rosiglitazone-induced sensitization of HCC cell lines (BEL-7402 and Huh-7 cells) to 5-FU.
  
  
  METHODS
  The 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) assay was used to evaluate cell viability. Western blotting analysis was performed to detect the protein expression (PPARgamma, PTEN, and COX-2) in BEL-7402 cells. Immunohistochemistry staining was used to examine the expression of PTEN in 100 advanced HCC tissues and paracancerous tissues. In addition, small interfering RNA was used to suppress PPARgamma, PTEN, and COX-2 expression.
  
  
  RESULTS
  Rosiglitazone facilitates the anti-tumor effect of 5-FU in HCC cell lines, which is mediated by the PPARgamma signaling pathway. Activation of PPARgamma by rosiglitazone increases PTEN expression and decreases COX-2 expression. Since distribution of PTEN in HCC tissues is significantly decreased compared with the paracancerous tissue, over-expression of PTEN by rosiglitazone enhances 5-FU-inhibited cell growth of HCC. Moreover, down-regulation of COX-2 is implicated in the synergistic effect of 5-FU.
  
  
  CONCLUSIONS
  Rosiglitazone sensitizes hepatocellular carcinoma cell lines to 5-FU antitumor activity through the activation of PPARgamma. The results suggest potential novel therapies for the treatment of advanced liver cancer.
authors.affiliation: Department of Hepatobiliary Surgery, the First Affiliated Hospital of Sun Yat-Sen University, Guangzhou 510080, China.
authors.forename: Liang-qi
authors.initials: LQ
authors.lastname: Cao
authors.forename: Xiao-li
authors.initials: XL
authors.lastname: Wang
authors.forename: Qian
authors.initials: Q
authors.lastname: Wang
authors.forename: Ping
authors.initials: P
authors.lastname: Xue
authors.forename: Xing-yuan
authors.initials: XY
authors.lastname: Jiao
authors.forename: He-ping
authors.initials: HP
authors.lastname: Peng
authors.forename: Hai-wu
authors.initials: HW
authors.lastname: Lu
authors.forename: Qiang
authors.initials: Q
authors.lastname: Zheng
authors.forename: Xi-lin
authors.initials: XL
authors.lastname: Chen
authors.forename: Xiao-hui
authors.initials: XH
authors.lastname: Huang
authors.forename: Xin-hui
authors.initials: XH
authors.lastname: Fu
authors.forename: Jing-song
authors.initials: JS
authors.lastname: Chen
mesh_terms: D000964:Antimetabolites, Antineoplastic / Q000627:therapeutic use*; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy*; D051546:Cyclooxygenase 2 / Q000096:biosynthesis; D015536:Down-Regulation / Q000187:drug effects; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D005472:Fluorouracil / Q000627:therapeutic use*; D006801:Humans; D008113:Liver Neoplasms / Q000188:drug therapy*; D047493:PPAR alpha / Q000187:drug effects*; D051059:PTEN Phosphohydrolase / Q000096:biosynthesis; D000077154:Rosiglitazone; D045162:Thiazolidinediones / Q000494:pharmacology*; D015533:Transcriptional Activation / Q000187:drug effects; D014407:Tumor Cells, Cultured
chemical_list: D000964:Antimetabolites, Antineoplastic; D047493:PPAR alpha; D045162:Thiazolidinediones; D000077154:Rosiglitazone; D051546:Cyclooxygenase 2; D051059:PTEN Phosphohydrolase; D005472:Fluorouracil
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