Inhibition of peroxisome proliferator-activated receptor gamma activity suppresses pancreatic cancer cell motility.
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.
Nakajima
Atsushi
A
Division of Gastroenterology, Yokohama City University School of Medicine, Yokohama, Japan.
Tomimoto
Ayako
A
Fujita
Koji
K
Sugiyama
Michiko
M
Takahashi
Hirokazu
H
Ikeda
Ikuko
I
Hosono
Kunihiro
K
Endo
Hiroki
H
Yoneda
Kyoko
K
Iida
Hiroshi
H
Inamori
Masahiko
M
Kubota
Kensuke
K
Saito
Satoru
S
Nakajima
Noriko
N
Wada
Koichiro
K
Nagashima
Yoji
Y
Nakagama
Hitoshi
H
D000818:Animals; D001549:Benzamides / Q000494:pharmacology*; D051177:Catenins; D015815:Cell Adhesion Molecules / Q000096:biosynthesis; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects* / Q000235:genetics; D006801:Humans; D008024:Ligands; D051379:Mice; D016513:Mice, SCID; D009362:Neoplasm Metastasis; D047495:PPAR gamma / Q000037:antagonists & inhibitors*; D010190:Pancreatic Neoplasms / Q000188:drug therapy* / Q000378:metabolism* / Q000473:pathology; D010750:Phosphoproteins / Q000096:biosynthesis; D011725:Pyridines / Q000494:pharmacology*; D034741:RNA, Small Interfering / Q000378:metabolism; D000077154:Rosiglitazone; D045162:Thiazolidinediones / Q000494:pharmacology*; D023041:Xenograft Model Antitumor Assays; D020764:cdc42 GTP-Binding Protein / Q000378:metabolism; D020830:rac1 GTP-Binding Protein / Q000378:metabolism; D000095002:Delta Catenin
D001549:Benzamides; D051177:Catenins; D015815:Cell Adhesion Molecules; D008024:Ligands; D047495:PPAR gamma; D010750:Phosphoproteins; D011725:Pyridines; D034741:RNA, Small Interfering; C458508:T 0070907; D045162:Thiazolidinediones; D000077154:Rosiglitazone; D020764:cdc42 GTP-Binding Protein; D020830:rac1 GTP-Binding Protein; D000095002:Delta Catenin