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[Cancer Research 65, 2251-2259, March 15, 2005]
© 2005 American Association for Cancer Research

Cell and Tumor Biology

Peroxisome Proliferator-Activated Receptor {gamma} Inhibition Prevents Adhesion to the Extracellular Matrix and Induces Anoikis in Hepatocellular Carcinoma Cells

Katherine L. Schaefer1, Koichiro Wada1,3, Hirokazu Takahashi4, Nobuyuki Matsuhashi5, Shin Ohnishi5, M. Michael Wolfe1, Jerrold R. Turner6, Atsushi Nakajima4, Steven C. Borkan2 and Lawrence J. Saubermann1

Sections of 1 Gastroenterology and 2 Nephrology, Boston Medical Center, Boston, Massachusetts; 3 Department of Pharmacology, Osaka University, Osaka, Japan; 4 Division of Gastroenterology, Yokohama City University School of Medicine, Yokohama, Japan; 5 Department of Medicine, University of Tokyo, Tokyo, Japan; and 6 Department of Pathology, University of Chicago, Chicago, Illinois

Requests for reprints: Katherine L. Schaefer, Boston Medical Center, Gastroenterology Section, 650 Albany Street, EBRC 520, Boston, MA 02118. Phone: 617-638-8332; Fax: 617-638-7785; E-mail: katherine.schaefer{at}bmc.org.

Activation of the nuclear transcription factor peroxisome proliferator-activated receptor {gamma} (PPAR{gamma}) inhibits growth and survival of hepatocellular carcinoma (HCC) cell lines. To further investigate the function of PPAR{gamma} in HCC, PPAR{gamma} expression patterns in primary tumors were examined, and the responses of two HCC cell lines to PPAR{gamma} activation and inhibition were compared. PPAR{gamma} expression was increased in HCC and benign-appearing peritumoral hepatocytes compared with remote benign hepatocytes. Both compound PPAR{gamma} inhibitors and PPAR{gamma} small interfering RNAs prevented HCC cell lines from adhering to the extracellular matrix. Loss of adhesion was followed by caspase-dependent apoptosis (anoikis). PPAR{gamma} inhibitors had no effect on initial ß1 integrin-mediated adhesion, or on total focal adhesion kinase levels but did reduce focal adhesion kinase phosphorylation. The PPAR{gamma} 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, PPAR{gamma} overexpression is present in HCC. Inhibition of PPAR{gamma} function causes HCC cell death by preventing adhesion and inducing anoikis-mediated apoptosis. PPAR{gamma} inhibitors represent a potential novel treatment approach to HCC.

Key Words: Peroxisome proliferator-activated receptor {gamma} • extracellular matrix • apoptosis • anoikis • hepatocellular carcinoma




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Copyright © 2005 by the American Association for Cancer Research.