title: Anoikis induction and inhibition of peritoneal metastasis of pancreatic cancer cells by a nuclear factor-κB inhibitor, (-)-DHMEQ.
abstract: The transcription factor nuclear factor-κB (NF-κB) plays a crucial role in pancreatic cancer (PC) progression. NF-κB is also involved in resistance to anoikis, a special type of apoptosis induced when cells are detached from the extracellular matrix or other cells. Anoikis resistance is related to the metastatic abilities of tumor cells; however, little is known about anoikis induction as it relates to inhibition of PC metastasis by NF-κB inhibitors. Here we used a specific NF-κB inhibitor, (-)-dehydroxymethylepoxyquinomicin (DHMEQ), to investigate anoikis induction and peritoneal metastasis suppression following NF-κB inhibition. We transduced Gluc, a secretory form of luciferase, into a PC cell line, AsPC-1 (AsPC-1-Gluc), for our in vivo experiments. (-)-DHMEQ induced anoikis in AsPC-1-Gluc cells as measured by cell survival assays and flow cytometry. The DNA-binding activity of p65 was enhanced immediately after cell detachment from culture dishes in ELISA assays. Some antiapoptotic proteins such as cellular inhibitor of apoptotic protein-1 were consequently upregulated on Western blots. (-)-DHMEQ prevented this increase in p65 activity and the subsequent expressions of antiapoptotic molecules. In a murine xenograft model, anoikis-resistant PC cell lines tended to metastasize to the peritoneum more than anoikis-sensitive cells, suggesting a correlation between anoikis sensitivity and peritoneal metastasis. (-)-DHMEQ successfully inhibited peritoneal metastasis of AsPC-1-Gluc cells. We monitored metastasis inhibition by ex vivo chemiluminescent detection of Gluc secreted from tumor cells into murine plasma and by in vivo imaging. Our results suggest that (-)-DHMEQ inhibited peritoneal dissemination by preventing anoikis resistance of PC cells.
authors.affiliation: Department of Gastroenterological Surgery I, Hokkaido University Graduate School of Medicine, Sapporo, Hokkaido, Japan.
authors.forename: Masanori
authors.initials: M
authors.lastname: Sato
authors.forename: Kazuaki
authors.initials: K
authors.lastname: Nakanishi
authors.forename: Sanae
authors.initials: S
authors.lastname: Haga
authors.forename: Masato
authors.initials: M
authors.lastname: Fujiyoshi
authors.forename: Motoi
authors.initials: M
authors.lastname: Baba
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Mino
authors.forename: Haruki
authors.initials: H
authors.lastname: Niwa
authors.forename: Hideki
authors.initials: H
authors.lastname: Yokoo
authors.forename: Kazuo
authors.initials: K
authors.lastname: Umezawa
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Ohmiya
authors.forename: Toshiya
authors.initials: T
authors.lastname: Kamiyama
authors.forename: Satoru
authors.initials: S
authors.lastname: Todo
authors.forename: Akinobu
authors.initials: A
authors.lastname: Taketomi
authors.forename: Michitaka
authors.initials: M
authors.lastname: Ozaki
mesh_terms: D000818:Animals; D023102:Anoikis / Q000187:drug effects*; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism; D001549:Benzamides / Q000494:pharmacology*; D045744:Cell Line, Tumor; D003512:Cyclohexanones / Q000494:pharmacology*; D004195:Disease Models, Animal; D015870:Gene Expression; D017930:Genes, Reporter; D006801:Humans; D051379:Mice; D057054:Molecular Imaging; D016328:NF-kappa B / Q000037:antagonists & inhibitors* / Q000378:metabolism; D010190:Pancreatic Neoplasms / Q000175:diagnosis / Q000378:metabolism* / Q000473:pathology*; D010534:Peritoneal Neoplasms / Q000188:drug therapy / Q000556:secondary*; D011485:Protein Binding; D051996:Transcription Factor RelA / Q000378:metabolism; D047368:Tumor Burden / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: D051017:Apoptosis Regulatory Proteins; D001549:Benzamides; D003512:Cyclohexanones; D016328:NF-kappa B; D051996:Transcription Factor RelA; C464444:dehydroxymethylepoxyquinomicin