Peroxisome proliferator-activated receptor gamma inhibition prevents adhesion to the extracellular matrix and induces anoikis in hepatocellular carcinoma cells.
Activation of the nuclear transcription factor peroxisome proliferator-activated receptor gamma (PPARgamma) inhibits growth and survival of hepatocellular carcinoma (HCC) cell lines. To further investigate the function of PPARgamma in HCC, PPARgamma expression patterns in primary tumors were examined, and the responses of two HCC cell lines to PPARgamma activation and inhibition were compared. PPARgamma expression was increased in HCC and benign-appearing peritumoral hepatocytes compared with remote benign hepatocytes. Both compound PPARgamma inhibitors and PPARgamma small interfering RNAs prevented HCC cell lines from adhering to the extracellular matrix. Loss of adhesion was followed by caspase-dependent apoptosis (anoikis). PPARgamma inhibitors had no effect on initial beta1 integrin-mediated adhesion, or on total focal adhesion kinase levels but did reduce focal adhesion kinase phosphorylation. The PPARgamma inhibitor T0070907 was significantly more efficient at causing cancer cell death than the activators troglitazone and rosiglitazone. T0070907 caused cell death by reducing adhesion and inducing anoikis, whereas the activators had no direct effect on adhesion and caused cell death at much higher concentrations. In conclusion, PPARgamma overexpression is present in HCC. Inhibition of PPARgamma function causes HCC cell death by preventing adhesion and inducing anoikis-mediated apoptosis. PPARgamma inhibitors represent a potential novel treatment approach to HCC.
Schaefer
Katherine L
KL
Section of Gastroenterology, Boston Medical Center, Boston, MA 02118, USA. katherine.schaefer@bmc.org
Wada
Koichiro
K
Takahashi
Hirokazu
H
Matsuhashi
Nobuyuki
N
Ohnishi
Shin
S
Wolfe
M Michael
MM
Turner
Jerrold R
JR
Nakajima
Atsushi
A
Borkan
Steven C
SC
Saubermann
Lawrence J
LJ
D000813:Anilides / Q000494:pharmacology; D023102:Anoikis / Q000187:drug effects* / Q000502:physiology*; D001549:Benzamides / Q000494:pharmacology; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D002448:Cell Adhesion / Q000187:drug effects; D048708:Cell Growth Processes / Q000187:drug effects / Q000502:physiology; D045744:Cell Line, Tumor; D048430:Cell Shape / Q000187:drug effects; D002839:Chromans / Q000494:pharmacology; D005109:Extracellular Matrix / Q000187:drug effects / Q000378:metabolism; D051417:Focal Adhesion Kinase 1; D051416:Focal Adhesion Protein-Tyrosine Kinases; D006801:Humans; D019012:Integrin beta1 / Q000096:biosynthesis; D008113:Liver Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D047495:PPAR gamma / Q000037:antagonists & inhibitors* / Q000096:biosynthesis; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D011725:Pyridines / Q000494:pharmacology; D000077154:Rosiglitazone; D045162:Thiazolidinediones / Q000494:pharmacology; D000077288:Troglitazone
C457499:2-chloro-5-nitrobenzanilide; D000813:Anilides; D001549:Benzamides; D002839:Chromans; D019012:Integrin beta1; D047495:PPAR gamma; D011725:Pyridines; C458508:T 0070907; D045162:Thiazolidinediones; D000077154:Rosiglitazone; D011505:Protein-Tyrosine Kinases; D051417:Focal Adhesion Kinase 1; D051416:Focal Adhesion Protein-Tyrosine Kinases; C496050:PTK2 protein, human; D000077288:Troglitazone