Upregulation of PTEN involved in rosiglitazone-induced apoptosis in human hepatocellular carcinoma cells.
OBJECTIVE
To investigate the effects of rosiglitazone, a peroxisome proliferator-activated receptor gamma (PPARgamma) agonist, on the expression of the phosphatase and tensin homologue deleted on chromosome 10 gene (PTEN) and cell growth in hepatocellular carcinoma cells, as well as the underlying mechanisms of these effects.


METHODS
RT-PCR and Western blotting analyses were performed to detect transcription and the expression of PTEN in Hep3B cells treated with rosiglitazone. 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide assay was used to evaluate cell growth. Flow cytometry, DNA fragmentation analysis, caspase enzymatic assay, and Hoechst 33258 staining were used to determine cell apoptosis. Furthermore, small interfering RNA was used to suppress PTEN expression.


RESULTS
Rosiglitazone increased the expression of PTEN in a dose- and time-dependent manner through the PPARgamma-dependent signal transduction pathway. PTEN upregulation was concomitant with a decreased level of Akt phosphorylation, subsequently resulting in cell growth inhibition and apoptosis in Hep3B cells. PTEN knockdown dramatically blocked these effects of rosiglitazone. Moreover, the exposure of cells to rosiglitazone activated caspases-9 and -3 during apoptotic proceeding.


CONCLUSIONS
Thus, upregulation of PTEN is involved in the inhibition of cell growth and the induction of cell apoptosis by rosiglitazone, suggesting that rosiglitazone may be useful in liver cancer therapy via apoptosis.
Cao
Liang-Qi
LQ
Department of Hepatobiliary Surgery, the First Affiliated Hospital of Sun Yat-Sen University, Guangzhou 510080, China.
Chen
Xi-Lin
XL
Wang
Qian
Q
Huang
Xiao-Hui
XH
Zhen
Mao-Chuan
MC
Zhang
Long-Juan
LJ
Li
Wen
W
Bi
Jiong
J
D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology; D006528:Carcinoma, Hepatocellular / Q000378:metabolism / Q000473:pathology; D002460:Cell Line; D006801:Humans; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D008113:Liver Neoplasms / Q000378:metabolism / Q000473:pathology; D047495:PPAR gamma / Q000378:metabolism; D051059:PTEN Phosphohydrolase / Q000235:genetics / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D000077154:Rosiglitazone; D015398:Signal Transduction / Q000502:physiology; D045162:Thiazolidinediones / Q000494:pharmacology*; D015854:Up-Regulation / Q000187:drug effects
D007004:Hypoglycemic Agents; D047495:PPAR gamma; D045162:Thiazolidinediones; D000077154:Rosiglitazone; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human