| Budget Amount *help |
¥3,200,000 (Direct Cost: ¥3,200,000)
Fiscal Year 2002: ¥800,000 (Direct Cost: ¥800,000)
Fiscal Year 2001: ¥700,000 (Direct Cost: ¥700,000)
Fiscal Year 2000: ¥1,700,000 (Direct Cost: ¥1,700,000)
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| Research Abstract |
Peroxisome proliferator-activated receptor-γ (PPAR-γ), a transcription factor belonging to the nuclearreceptor superfamily, forms functional heterodimers with the retinoid X receptor. Synthetic PPAR-γ ligands have been shown to inhibit the growth of several human tumor cell lines and to induce growth arrest and differentiation in primary cultures of human liposarcoma, colon cancer, and breast cancer cells in vitro and in vivo. The aim of this study was to examine whether PPAR-γ is expressed at high level in human pancreatic cancer cells, and its ligand can inhibit cellular growth through terminal differentiation of pancreatic cancer cells. In addition, we also examined whether thiazol idinedione (TZD), a potent PPAR-γ ligand. could modulate the E-cadherin/β-catenin system in human pancreatic cancer cells. First, in this study we investigated the expression of PPAR-γ in five pancreatic cancer cell lines: Capan-1(well differentiated adenocarcinema), AsPC-1(moderately differentiated adeno
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carcinoma), BxPC-3(moderately differentiated adenocarcinoma), Panc-1(poorly differentiated adenocarcinoma), and MIAPaCa-2(undifferentiated carcinoma). All five expressed PPAR-γ mRNA and protein, shown respectively on RT-PCR and Western blotting analisis. Clonogenic assaya showed that TZD completely inhibits colony formation of these cells at a concentration of 10 μ M. Moreover, treatment of these cells with 10 μM TZD resulted in GO/G1 cell cyclearrest. According to Western blotting, TZD markedly increased differentiation markers including E-cadherin and CEA, while β-catenin did not change significantly. In untreated cells, fluorescence immunostaining demonstrated β-catenin predominantly in the cytoplasm and/or nucleus: in TZD-treated cells, β-caten in localization had dramatically shifted to the plasma membrane, in association with increased E-cadherin at this site. Thus, a PPAR-γ ligand appears to participate not only in induction of cell growth and differentiation in pancreatic cancer cells, but also in the regulation of E-cadherin/β-catenin system. Such ligands may prove clinically useful as cytostatic anticancer agents. Less
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