title: Indometacin ameliorates high glucose-induced proliferation and invasion via modulation of e-cadherin in pancreatic cancer cells.
abstract: Indometacin, an inhibitor of cyclooxygenase-2 (COX-2), has been shown to exert anticancer effects in a variety of cancers. However, the effect and mechanism of indometacin on high glucose (HG)-induced proliferation and invasion of pancreatic cancer (PC) cells remain unclear. Multiple lines of evidence suggest that a large portion of pancreatic cancer (PC) patients suffer from either diabetes or HG which contributing PC progression. In this study, we report that indometacin down-regulated HG-induced proliferation and invasion via up-regulating E-cadherin but not COX-2 in PC cells. Additionally, the E-cadherin transcriptional repressors, Snail and Slug, were also involved in the process. Furthermore, the proliferation and invasion of PC cells, incubated in HG medium and treated with indometacin were significantly increased when E-cadherin was knocked down (Si-E-cad). Moreover, the protein levels of MMP-2, MMP-9, and VEGF were increased in PC cells transfected with Si-E-cad. Finally, the activation of the PI3K/AKT/GSK-3β signaling pathway was demonstrated to be involved in indometacin reversing HG-induced cell proliferation and invasion in PC cells. In conclusion, these results suggest that indometacin plays a key role in down-regulating HG-induced proliferation and invasion in PC cells. Our findings indicate that indometacin could be used as a novel therapeutic strategy to treat PC patients who simultaneously suffer from diabetes or HG.
authors.affiliation: Department of Hepatobiliary Surgery, First Affiliated Hospital of Medical College, Xi'an Jiaotong University, Xi'an 710061, Shaanxi, China.
authors.forename: Liang
authors.initials: L
authors.lastname: Han
authors.affiliation: Emergency Department, First Affiliated Hospital of Medical College, Xi'an Jiaotong University, Xi'an 710061, Shaanxi, China.
authors.forename: Bo
authors.initials: B
authors.lastname: Peng
authors.affiliation: Department of Hepatobiliary Surgery, First Affiliated Hospital of Medical College, Xi'an Jiaotong University, Xi'an 710061, Shaanxi, China.
authors.forename: Qingyong
authors.initials: Q
authors.lastname: Ma
authors.affiliation: Department of Oncology, First Affiliated Hospital of Medical College, Xi'an Jiaotong University, Xi'an 710061, Shaanxi, China.
authors.forename: Jiguang
authors.initials: J
authors.lastname: Ma
authors.affiliation: Department of Hepatobiliary Surgery, First Affiliated Hospital of Medical College, Xi'an Jiaotong University, Xi'an 710061, Shaanxi, China.
authors.forename: Juntao
authors.initials: J
authors.lastname: Li
authors.affiliation: Department of Hepatobiliary Surgery, First Affiliated Hospital of Medical College, Xi'an Jiaotong University, Xi'an 710061, Shaanxi, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Li
authors.affiliation: Department of Hepatobiliary Surgery, First Affiliated Hospital of Medical College, Xi'an Jiaotong University, Xi'an 710061, Shaanxi, China.
authors.forename: Wanxing
authors.initials: W
authors.lastname: Duan
authors.affiliation: Department of Hepatobiliary Surgery, First Affiliated Hospital of Medical College, Xi'an Jiaotong University, Xi'an 710061, Shaanxi, China.
authors.forename: Chao
authors.initials: C
authors.lastname: Chen
authors.affiliation: Department of Hepatobiliary Surgery, First Affiliated Hospital of Medical College, Xi'an Jiaotong University, Xi'an 710061, Shaanxi, China.
authors.forename: Jiangbo
authors.initials: J
authors.lastname: Liu
authors.affiliation: Department of Hepatobiliary Surgery, First Affiliated Hospital of Medical College, Xi'an Jiaotong University, Xi'an 710061, Shaanxi, China.
authors.forename: Qinhong
authors.initials: Q
authors.lastname: Xu
authors.affiliation: Department of Pharmaceutical Sciences, North Dakota State University, Fargo, ND 58105, USA.
authors.forename: Kyle
authors.initials: K
authors.lastname: Laporte
authors.affiliation: Department of Pharmaceutical Sciences, North Dakota State University, Fargo, ND 58105, USA.
authors.forename: Zehui
authors.initials: Z
authors.lastname: Li
authors.affiliation: Department of Pharmaceutical Sciences, North Dakota State University, Fargo, ND 58105, USA.
authors.forename: Erxi
authors.initials: E
authors.lastname: Wu
mesh_terms: D015820:Cadherins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002867:Chromones / Q000494:pharmacology; D015536:Down-Regulation / Q000187:drug effects*; D005947:Glucose / Q000494:pharmacology; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D006801:Humans; D007213:Indomethacin / Q000494:pharmacology*; D009025:Morpholines / Q000494:pharmacology; D010190:Pancreatic Neoplasms / Q000378:metabolism / Q000473:pathology; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors / Q000378:metabolism; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D015820:Cadherins; D002867:Chromones; D005947:Glucose; D038362:Glycogen Synthase Kinase 3; D000071679:Glycogen Synthase Kinase 3 beta; D007213:Indomethacin; D009025:Morpholines; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt; D034741:RNA, Small Interfering; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; C000605506:GSK3B protein, human