title: Signaling pathway involved in cyclooxygenase-2 up-regulation by hepatocyte growth factor in endometrial cancer cells.
abstract: Hepatocyte growth factor (HGF) is up-regulated in tissue repair and has been implicated in playing a role in this process through its anti-apoptotic and proliferative activities. Cyclooxygenase-2 (COX-2) is an inducible enzyme in the biosynthetic pathway of prostaglandins, and its activation has been shown to play an important role in cell growth. We previously reported that HGF significantly inhibited anoikis, possibly through the up-regulation of COX-2 expression in the endometrial RL95-2 cancer cell line. Here, we report that i) treatment of RL95-2 cells with HGF resulted in phosphorylation of the HGF receptor c-Met, activation of Akt and IκB, translocation of NF-κB into the nucleus, and up-regulation of COX-2 mRNA; ii) the IκB-α phosphorylation inhibitor BAY11-7082 and the selective COX-2 inhibitor CAY10452 blocked HGF-mediated anoikis resistance in RL95-2 cells; and iii) HGF induced migration and invasion in RL95-2 cells, while the phosphatidylinositol 3-kinase (PI3K) inhibitor LY294002 and CAY10452 blocked these effects of HGF stimulation. Our data suggest that HGF possesses chemotactic ability, has anti-apoptosis action, and induces cellular infiltration via the PI3K/Akt pathway; it also triggers NF-κB activation and up-regulates COX-2 gene expression in endometrial cancer cells.
authors.affiliation: Department of Obstetrics and Gynecology, Nara Medical University, Kashihara, Nara 634-8522, Japan.
authors.forename: Yoriko
authors.initials: Y
authors.lastname: Yoshizawa
authors.forename: Yoshihiko
authors.initials: Y
authors.lastname: Yamada
authors.forename: Seiji
authors.initials: S
authors.lastname: Kanayama
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Shigetomi
authors.forename: Ryuji
authors.initials: R
authors.lastname: Kawaguchi
authors.forename: Shozo
authors.initials: S
authors.lastname: Yoshida
authors.forename: Akira
authors.initials: A
authors.lastname: Nagai
authors.forename: Naoto
authors.initials: N
authors.lastname: Furukawa
authors.forename: Hidekazu
authors.initials: H
authors.lastname: Oi
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Kobayashi
mesh_terms: D023102:Anoikis / Q000502:physiology; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000502:physiology; D051546:Cyclooxygenase 2 / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism; D016889:Endometrial Neoplasms / Q000201:enzymology / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D017228:Hepatocyte Growth Factor / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D006801:Humans; D020672:I-kappa B Proteins / Q000378:metabolism; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D012333:RNA, Messenger / Q000096:biosynthesis / Q000097:blood; D020794:Receptor Protein-Tyrosine Kinases / Q000378:metabolism; D015398:Signal Transduction; D015854:Up-Regulation
chemical_list: D020672:I-kappa B Proteins; D012333:RNA, Messenger; D017228:Hepatocyte Growth Factor; D051546:Cyclooxygenase 2; C080835:RON protein; D020794:Receptor Protein-Tyrosine Kinases; D051057:Proto-Oncogene Proteins c-akt