Rosiglitazone sensitizes hepatocellular carcinoma cell lines to 5-fluorouracil antitumor activity through activation of the PPARγ signaling pathway
Aim: Resistance to 5-fluorouracil (5-FU) is a major cause of chemotherapy failure in advanced hepatocellular carcinoma (HCC). Rosiglitazone, a peroxisome proliferator-activated receptor y (PPARy) agonist, has a crucial role in growth inhibition and induction of apoptosis in several carcinoma cell li...
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Published in | Acta pharmacologica Sinica Vol. 30; no. 9; pp. 1316 - 1322 |
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Main Authors | , , , , , , , , , , , |
Format | Journal Article |
Language | English |
Published |
Nature Publishing Group
01.09.2009
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Subjects | |
Online Access | Get full text |
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Summary: | Aim: Resistance to 5-fluorouracil (5-FU) is a major cause of chemotherapy failure in advanced hepatocellular carcinoma (HCC). Rosiglitazone, a peroxisome proliferator-activated receptor y (PPARy) 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 (MI-I) assay was used to evaluate cell viability. Western blotting analysis was performed to detect the protein expression (PPARy, 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 PPARy, PTEN, and COX-2 expression. Results: Rosiglitazone facilitates the anti-tumor effect of 5-FU in HCC cell lines, which is mediated by the PPARy signaling pathway. Activation of PPARy 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. Conclusion: Rosiglitazone sensitizes hepatocellular carcinoma cell lines to 5-FU antitumor activity through the activation of PPARy. The results suggest potential novel therapies for the treatment of advanced liver cancer. |
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Bibliography: | 5-fluorourac TQ463.5 PPARy Q257 PTEN rosiglitazone rosiglitazone; hepatocellular carcinoma; PTEN; PPARy; 5-fluorourac hepatocellular carcinoma 31-1347/R These authors contributed equally to this work. |
ISSN: | 1671-4083 1745-7254 |
DOI: | 10.1038/aps.2009.119 |