title: Novel involvement of leukotriene B₄ receptor 2 through ERK activation by PP2A down-regulation in leukotriene B₄-induced keratin phosphorylation and reorganization of pancreatic cancer cells.
abstract: Perinuclear reorganization via phosphorylation of specific serine residues in keratin is involved in the deformability of metastatic cancer cells. The level of leukotriene B₄ is high in pancreatic cancers. However, the roles of LTB₄ and its cognate receptors in keratin reorganization of pancreatic cancers are not known. LTB₄ dose-dependently induced phosphorylation and reorganization of Keratin 8 (K8) and these processes were reversed by LY255283 (BLT2 antagonist). BLT2 agonists such as Comp A and 15(S)-HETE also induced phosphorylation of serine 431 in K8. Moreover, Comp A-induced K8 phosphorylation and reorganization were blocked by LY255283. Gene silencing of BLT2 suppressed Comp A-induced K8 phosphorylation and reorganization in PANC-1 cells. Over-expression of BLT2 promoted K8 phosphorylation. Comp A promoted the migration of PANC-1 cells in a dose-dependent manner, and LY255283 blocked Comp A-induced migration, respectively. PD98059 (ERK inhibitor) suppressed Comp A-induced phosphorylation of serine 431 and reorganization of K8. Gene silencing of BLT2 suppressed the expression of pERK, and over-expression of BLT2 increased the expression of pERK even without Comp A. Comp A induced the expression of active ERK (pERK) and BLT2. These inductions were blocked by PD98059. Comp A decreased PP2A expression and hindered the binding of PP2A to the K8, leading to the activation of ERK. PD98059 suppressed the Comp A-induced migration of PANC-1 cells and BLT2 over-expression-induced migration of PANC-1 cells. Overall, these results suggest that BLT2 is involved in LTB(4)-induced phosphorylation and reorganization through ERK activation by PP2A downregulation, leading to increased migration of PANC-1 cells.
authors.affiliation: College of Pharmacy, Dongguk University, Goyang 410-820, Republic of Korea.
authors.forename: Mi Kyung
authors.initials: MK
authors.lastname: Park
authors.forename: Youngran
authors.initials: Y
authors.lastname: Park
authors.forename: Jaegal
authors.initials: J
authors.lastname: Shim
authors.forename: Hye Ja
authors.initials: HJ
authors.lastname: Lee
authors.forename: Sanghee
authors.initials: S
authors.lastname: Kim
authors.forename: Chang Hoon
authors.initials: CH
authors.lastname: Lee
mesh_terms: D018685:Anesthetics, Inhalation / Q000494:pharmacology; D015153:Blotting, Western; D002448:Cell Adhesion / Q000187:drug effects; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D015536:Down-Regulation; D004789:Enzyme Activation; D004987:Ethers / Q000494:pharmacology; D005419:Flavonoids / Q000494:pharmacology; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D006801:Humans; D006845:Hydrocarbons, Fluorinated / Q000494:pharmacology; D047468:Immunoprecipitation; D053533:Keratin-8 / Q000378:metabolism*; D007975:Leukotriene B4 / Q000494:pharmacology*; D048052:Mitogen-Activated Protein Kinase 3 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D010190:Pancreatic Neoplasms / Q000378:metabolism* / Q000473:pathology; D010766:Phosphorylation / Q000187:drug effects; D054648:Protein Phosphatase 2 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics; D034741:RNA, Small Interfering / Q000235:genetics; D018102:Receptors, Leukotriene B4 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D012694:Serine / Q000737:chemistry / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D014407:Tumor Cells, Cultured
chemical_list: D018685:Anesthetics, Inhalation; D004987:Ethers; D005419:Flavonoids; D006845:Hydrocarbons, Fluorinated; D053533:Keratin-8; C485878:LTB4R2 protein, human; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D018102:Receptors, Leukotriene B4; D007975:Leukotriene B4; D012694:Serine; C078742:fluoromethyl 2,2-difluoro-1-(trifluoromethyl)vinyl ether; D048052:Mitogen-Activated Protein Kinase 3; D054648:Protein Phosphatase 2; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one