Troglitazone inhibits tumor growth in hepatocellular carcinoma in vitro and in vivo.
Peroxisome proliferator-activated receptor gamma (PPARgamma) has been implicated in the differentiation and growth inhibition of cancer cells. We examined the effects of PPARgamma activation by troglitazone on hepatocellular carcinoma (HCC) cell growth, proliferation, and apoptosis in vitro and in vivo. We also studied relationships between PPARgamma activation and cyclooxygenase-2 (COX-2) expression. Human HCC cell lines Huh7 and Hep3B were cultured in the presence or absence of troglitazone. Cell growth was determined via WST-1 assay, proliferation by cell cycle analysis and proliferating cell nuclear antigen (PCNA) Western blotting, and apoptosis by flow cytometry and TUNEL. Tumor growth after subcutaneous implantation of Huh7 cells in nude mice was monitored, and the effects of treatment with troglitazone were determined. In resected HCCs, PPARgamma expression was less compared with the histologically normal surrounding liver. In cultures of Hep3B and Huh7 cells, basal expression of PPARgamma was relatively low, but troglitazone caused dose-dependent induction of PPARgamma expression. Cell cycle analysis revealed a decreased proportion of cells in S phase, with arrest at G0/G1. Concomitant downregulation of PCNA and an increase in TUNEL staining, cells were consistent with decreased proliferation and induction of apoptosis by troglitazaone. Troglitazone-mediated PPARgamma activation also suppressed COX-2 expression and induced p27 in HCC cells. Administration of troglitazone to Huh7 tumor-bearing mice significantly reduced tumor growth and caused tumor regression. In conclusion, collectively, these results indicate that PPARgamma could be a regulator of cell survival and growth in HCC. PPARgamma therefore represents a putative molecular target for chemopreventive therapy or inhibition of liver cancer growth.
Yu
Jun
J
Storr Liver Unit, Westmead Millennium Institute, University of Sydney, Westmead Hospital, Westmead, NSW 2145, Australia.
Qiao
Liang
L
Zimmermann
Lars
L
Ebert
Matthias P A
MP
Zhang
Hongxia
H
Lin
Wendy
W
Röcken
Christoph
C
Malfertheiner
Peter
P
Farrell
Geoffrey C
GC
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis; D002453:Cell Cycle / Q000187:drug effects; D002470:Cell Survival; D002839:Chromans / Q000494:pharmacology* / Q000627:therapeutic use; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000096:biosynthesis; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000096:biosynthesis; D051546:Cyclooxygenase 2 / Q000032:analysis / Q000235:genetics; D005260:Female; D006801:Humans; D008113:Liver Neoplasms / Q000188:drug therapy* / Q000473:pathology; D008114:Liver Neoplasms, Experimental / Q000188:drug therapy; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008875:Middle Aged; D047495:PPAR gamma / Q000187:drug effects* / Q000235:genetics / Q000502:physiology; D012333:RNA, Messenger / Q000032:analysis; D045162:Thiazolidinediones / Q000494:pharmacology* / Q000627:therapeutic use; D000077288:Troglitazone; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; C493956:CDKN1A protein, human; D002839:Chromans; D050759:Cyclin-Dependent Kinase Inhibitor p21; D047495:PPAR gamma; D012333:RNA, Messenger; D045162:Thiazolidinediones; D050760:Cyclin-Dependent Kinase Inhibitor p27; D051546:Cyclooxygenase 2; D000077288:Troglitazone