title: Absence of CD9 enhances adhesion-dependent morphologic differentiation, survival, and matrix metalloproteinase-2 production in small cell lung cancer cells.
abstract: While adhering to extracellular matrix proteins in vitro and in vivo, small cell lung cancer (SCLC) cells frequently show morphologic differentiation and are protected from apoptosis. Integrin beta(1)-mediated protein phosphorylation is suggested to be an essential signaling event in these processes. CD9 is an almost ubiquitously expressed tetraspanin protein that suppresses tumor progression by regulating cell motility and signaling through complex formation with beta(1) integrins. We reported previously that, among tetraspanins, CD9 is selectively absent in most SCLC cells and that ectopic expression of CD9 suppresses their motility. Here, we show that the ectopic expression of CD9 suppressed neurite-like process outgrowth and promoted apoptotic death of SCLC cells that were adherent to fibronectin in serum-starved conditions. This correlated with attenuation of adhesion-dependent phosphorylation of Akt but not that of focal adhesion kinase or c-Jun NH(2)-terminal kinase. Treatment of CD9(-) parent cells with a phosphatidylinositol 3-kinase (PI3K) inhibitor, LY294002, inhibited process outgrowth and survival, suggesting that PI3K/Akt signaling is required for the morphologic change and cell survival. Production of matrix metalloproteinase (MMP)-2 was likewise suppressed in the CD9 transfectants and in LY294002-treated parent cells. These results suggest that the absence of CD9 in SCLC cells may contribute to postadhesive morphologic differentiation, survival, and MMP-2 production via PI3K/Akt pathway.
authors.affiliation: Department of Respiratory Medicine, Allergy and Rheumatic Diseases, Osaka University Graduate School of Medicine, Osaka, Japan.
authors.forename: Yoshiyuki
authors.initials: Y
authors.lastname: Saito
authors.forename: Isao
authors.initials: I
authors.lastname: Tachibana
authors.forename: Yoshito
authors.initials: Y
authors.lastname: Takeda
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Yamane
authors.forename: Ping
authors.initials: P
authors.lastname: He
authors.forename: Mayumi
authors.initials: M
authors.lastname: Suzuki
authors.forename: Seigo
authors.initials: S
authors.lastname: Minami
authors.forename: Takashi
authors.initials: T
authors.lastname: Kijima
authors.forename: Mitsuhiro
authors.initials: M
authors.lastname: Yoshida
authors.forename: Toru
authors.initials: T
authors.lastname: Kumagai
authors.forename: Tadashi
authors.initials: T
authors.lastname: Osaki
authors.forename: Ichiro
authors.initials: I
authors.lastname: Kawase
mesh_terms: D015703:Antigens, CD / Q000502:physiology*; D017209:Apoptosis / Q000235:genetics / Q000502:physiology*; D018288:Carcinoma, Small Cell / Q000378:metabolism* / Q000473:pathology; D002448:Cell Adhesion; D045744:Cell Line, Tumor / Q000378:metabolism / Q000648:ultrastructure; D048429:Cell Size; D022081:Cell Surface Extensions / Q000648:ultrastructure; D004790:Enzyme Induction; D005353:Fibronectins / Q000494:pharmacology; D006801:Humans; D008175:Lung Neoplasms / Q000378:metabolism* / Q000473:pathology; D020778:Matrix Metalloproteinase 2 / Q000096:biosynthesis / Q000235:genetics; D020780:Matrix Metalloproteinase 9 / Q000096:biosynthesis* / Q000235:genetics; D008562:Membrane Glycoproteins / Q000172:deficiency / Q000502:physiology*; D009363:Neoplasm Proteins / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D019869:Phosphatidylinositol 3-Kinases / Q000502:physiology; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010766:Phosphorylation; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011499:Protein Processing, Post-Translational; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D034741:RNA, Small Interfering / Q000494:pharmacology; D011993:Recombinant Fusion Proteins / Q000502:physiology; D015398:Signal Transduction / Q000187:drug effects; D060245:Tetraspanin 29
chemical_list: D015703:Antigens, CD; D005353:Fibronectins; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9; D008562:Membrane Glycoproteins; D009363:Neoplasm Proteins; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt; D034741:RNA, Small Interfering; D011993:Recombinant Fusion Proteins; D060245:Tetraspanin 29; C554869:CD9 protein, human; C494918:AKT1 protein, human