A new strategy for the therapy of pancreatic cancer by a specific ligand of peroxisome proliferator-activated receptor-gamma

过氧化物酶体增殖物激活受体-γ特异性配体治疗胰腺癌的新策略

• 批准号: 12671213
• 负责人: OHTA Tetsuo
• 金额: $ 2.05万
• 依托单位: Kanazawa University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2000
• 资助国家: 日本
• 起止时间: 2000 至 2002
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-12671213/
• 关键词: peroxisome proliferator-activated receptor-γ; thiazolidinedione (TZD); pancreatic cancer; differentiation therapy; G1 growth arrest; p21Waf-1 protein; E-cadherin protein; β-catenin; Gl growth arrest; β-catenin蛋白; thiazolidinedion(TZD); 大腸癌; 足場

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 … More 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

过氧化物酶体增殖物激活受体-γ（Peroxisome proliferator-activated receptor-γ，PPAR-γ）是核受体超家族的一种转录因子，与维甲酸X受体形成功能性异源二聚体。已显示合成的PPAR-γ配体抑制几种人肿瘤细胞系的生长，并在体外和体内诱导人脂肪肉瘤、结肠癌和乳腺癌细胞的原代培养物中的生长停滞和分化。本研究的目的是检测人胰腺癌细胞中是否存在高水平的过氧化物酶体增殖物激活受体-γ（PPAR-γ）表达，以及其配体是否能通过胰腺癌细胞的终末分化抑制细胞生长。此外，我们还研究了噻唑烷二酮（TZD），一种有效的PPAR-γ配体。可调节人胰腺癌细胞中的E-cadherin/β-catenin系统。首先，在本研究中，我们研究了五种胰腺癌细胞系中PPAR-γ的表达：Capan-1（高分化腺癌），AsPC-1（中分化腺癌）， ...更多信息 癌）、BxPC-3（中等分化腺癌）、Panc-1（低分化腺癌）和MIAPaCa-2（未分化癌）。RT-PCR和Westernblotting分析显示，5种细胞均表达PPAR-γ mRNA和蛋白。克隆形成实验表明，TZD在10 μ M浓度下完全抑制这些细胞的集落形成。此外，用10 μM TZD处理这些细胞导致GO/G1细胞周期停滞。Western blotting结果显示，TZD可显著增加E-cadherin、CEA等分化标志物的表达，而β-catenin表达无明显变化。在未处理的细胞中，荧光免疫染色显示β-连环蛋白主要存在于细胞质和/或细胞核中：在TZD处理的细胞中，定位的β-连环蛋白显著转移到质膜，与该位点的E-钙粘蛋白增加相关。因此，PPAR-γ配体似乎不仅参与胰腺癌细胞生长和分化的诱导，而且还参与E-cadherin/β-catenin系统的调节。这样的配体可以证明在临床上可用作细胞抑制抗癌剂。少

项目成果

Ayman Elnemr: "PPAR-gamma induces growth arrest and differentiation markers of human pancreartic cancer cells"Int J Oncol. 17. 1157-1164 (2000)

Ayman Elnemr：“PPAR-gamma 诱导人胰腺癌细胞的生长停滞和分化标记物”Int J Oncol。

Ohta T., Elnemr A., Yamamoto M., et al.: "Thiazolidine- dione, a peroxisome proliferator-activated receptor-γ ligand, modulates the E-cadherin/β-catenin system in a human pancreatic cancer cell line, BxPG-3."Int J Oncol. 21. 37-42 (2002)

Ohta T.、Elnemr A.、Yamamoto M. 等人：“噻唑烷二酮是一种过氧化物酶体增殖物激活受体-γ 配体，可调节人胰腺癌细胞系中的 E-钙粘蛋白/β-连环蛋白系统，BxPG -3。《国际肿瘤学杂志》21. 37-42 (2002)

Elnemr A., Ohta T., Iwata K., et al.: "PPAR-γ ligand induces growth arrest and differentiation markers of human pancreatic cancer cells"Int J Oncol. 17. 1157-1164 (2000)

Elnemr A.、Ohta T.、Iwata K. 等：“PPAR-γ 配体诱导人胰腺癌细胞的生长停滞和分化标记”Int J Oncol. 17. 1157-1164 (2000)

Ayman Elnemr et al.: "PPAR-gamma induces growth arrest and diffenetiation markers of human pancreatic cancer cells"International Journal of Oncology. 17. 1157-1164 (2000)

Ayman Elnemr 等人：“PPAR-gamma 诱导人类胰腺癌细胞的生长停滞和分化标记物”国际肿瘤学杂志。

Tetsuo Ohta, et al.: "Thiazolidinedione, a peroxisome proliferator-activated receptor-γ ligand, modulate the E-cadherin/β-catenin system in a human pancreatic cancer cell line, BxPC-3"International Journal of Oncology. 21. 37-42 (2002)

Tetsuo Ohta 等人：“噻唑烷二酮是一种过氧化物酶体增殖物激活受体-γ 配体，可调节人胰腺癌细胞系 BxPC-3 中的 E-钙粘蛋白/β-连环蛋白系统”《国际肿瘤学杂志》21. 37。 -42 (2002)