Rosiglitazone sensitizes hepatocellular carcinoma cell lines to 5-fluorouracil antitumor activity through activation of the PPARgamma signaling pathway.
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.
Cao
Liang-qi
LQ
Department of Hepatobiliary Surgery, the First Affiliated Hospital of Sun Yat-Sen University, Guangzhou 510080, China.
Wang
Xiao-li
XL
Wang
Qian
Q
Xue
Ping
P
Jiao
Xing-yuan
XY
Peng
He-ping
HP
Lu
Hai-wu
HW
Zheng
Qiang
Q
Chen
Xi-lin
XL
Huang
Xiao-hui
XH
Fu
Xin-hui
XH
Chen
Jing-song
JS
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
D000964:Antimetabolites, Antineoplastic; D047493:PPAR alpha; D045162:Thiazolidinediones; D000077154:Rosiglitazone; D051546:Cyclooxygenase 2; D051059:PTEN Phosphohydrolase; D005472:Fluorouracil
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