Nakajima Atsushi, Tomimoto Ayako, Fujita Koji, Sugiyama Michiko, Takahashi Hirokazu, Ikeda Ikuko, Hosono Kunihiro, Endo Hiroki, Yoneda Kyoko, Iida Hiroshi, Inamori Masahiko, Kubota Kensuke, Saito Satoru, Nakajima Noriko, Wada Koichiro, Nagashima Yoji, Nakagama Hitoshi
Division of Gastroenterology, Yokohama City University School of Medicine, Yokohama, Japan.
Cancer Sci. 2008 Oct;99(10):1892-900. doi: 10.1111/j.1349-7006.2008.00904.x.
Peroxisome proliferator-activated receptor gamma (PPARgamma) is a ligand-activated transcription factor that has been implicated in the carcinogenesis and progression of various solid tumors, including pancreatic carcinomas. We aimed to clarify the role of this receptor in pancreatic cell motility in vitro and in metastasis in vivo. Cell motility was examined by assaying transwell migration and wound filling in Capan-1 and Panc-1 pancreatic cancer cells, with or without the PPARgamma-specific inhibitor T0070907. A severe combined immunodeficiency xenograft metastasis model was used to examine the in vivo effect of PPARgamma inhibition on pancreatic cancer metastasis. In both transwell-migration and wound-filling assays, inhibition of PPARgamma activity suppressed pancreatic cell motility without affecting in vitro cell proliferation. Inhibition of PPARgamma also suppressed liver metastasis in vivo in metastatic mice. In PPARgamma-inhibited cells, p120 catenin accumulation was induced predominantly in cell membranes, and the Ras-homologous GTPases Rac1 and Cdc42 were inactive. Inhibition of PPARgamma in pancreatic cancer cells decreased cell motility by altering p120ctn localization and by suppressing the activity of the Ras-homologous GTPases Rac1 and Cdc42. Based on these findings, PPARgamma could function as a novel target for the therapeutic control of cancer cell invasion or metastasis.
过氧化物酶体增殖物激活受体γ（PPARγ）是一种配体激活的转录因子，与包括胰腺癌在内的多种实体瘤的发生和进展有关。我们旨在阐明该受体在体外胰腺细胞运动及体内转移中的作用。通过检测Capan-1和Panc-1胰腺癌细胞在有或无PPARγ特异性抑制剂T0070907情况下的Transwell迁移和伤口愈合情况来检测细胞运动。使用严重联合免疫缺陷异种移植转移模型来检测PPARγ抑制对胰腺癌转移的体内作用。在Transwell迁移和伤口愈合试验中，PPARγ活性的抑制均抑制了胰腺细胞运动，而不影响体外细胞增殖。PPARγ的抑制在体内也抑制了转移性小鼠的肝转移。在PPARγ抑制的细胞中，p120连环蛋白主要在细胞膜上积累，并且Ras同源GTP酶Rac1和Cdc42无活性。胰腺癌细胞中PPARγ的抑制通过改变p120ctn的定位以及抑制Ras同源GTP酶Rac1和Cdc42的活性而降低细胞运动。基于这些发现，PPARγ可作为癌细胞侵袭或转移治疗控制的新靶点。
