open access

https://doi.org/10.14943/doctoral.k11596

https://hdl.handle.net/2115/57776

NF-κB阻害剤 (-)-DHMEQによる膵癌細胞のアノイキス誘導及び腹膜転移阻害

英語

Peritoneal metastasis

2014-12-25

Hokkaido University

333-343 [11] p.

共著: Nakanishi, Kazuaki; Haga, Sanae; Fujiyoshi, Masato; Baba, Motoi; Mino, Kazuhiro; Yimin; Niwa, Haruki; Yokoo, Hideki; Umezawa, Kazuo; Ohmiya, Yoshihiro; Kamiyama, Toshiya; Todo, Satoru; Taketomi, Akinobu; Ozaki, Michitaka. 配架番号：2120

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.

2014-12-25

甲第11596号

博士(医学)

(主査) 教授 平野 聡, 教授 武冨 紹信, 教授 田中 伸哉, 教授 山下 啓子

医学研究科（高次診断治療学専攻）

博士論文

Version of Record