Inhibition of peroxisome proliferator‐activated receptor γ activity suppresses pancreatic cancer cell motility

Peroxisome proliferator‐activated receptor γ (PPARγ) 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 PPARγ‐specific inhibitor T0070907. A severe combined immunodeficiency xenograft metastasis model was used to examine the in vivo effect of PPARγ inhibition on pancreatic cancer metastasis. In both transwell‐migration and wound‐filling assays, inhibition of PPARγ activity suppressed pancreatic cell motility without affecting in vitro cell proliferation. Inhibition of PPARγ also suppressed liver metastasis in vivo in metastatic mice. In PPARγ‐inhibited cells, p120 catenin accumulation was induced predominantly in cell membranes, and the Ras‐homologous GTPases Rac1 and Cdc42 were inactive. Inhibition of PPARγ 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, PPARγ could function as a novel target for the therapeutic control of cancer cell invasion or metastasis. (Cancer Sci 2008; 99: 1892–1900)