t-0070907 and Pancreatic-Neoplasms

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.

Topics: Animals; Benzamides; Catenins; cdc42 GTP-Binding Protein; Cell Adhesion Molecules; Cell Line, Tumor; Cell Movement; Delta Catenin; Humans; Ligands; Mice; Mice, SCID; Neoplasm Metastasis; Pancreatic Neoplasms; Phosphoproteins; PPAR gamma; Pyridines; rac1 GTP-Binding Protein; RNA, Small Interfering; Rosiglitazone; Thiazolidinediones; Xenograft Model Antitumor Assays