title: TF/FVIIa/PAR2 promotes cell proliferation and migration via PKCα and ERK-dependent c-Jun/AP-1 pathway in colon cancer cell line SW620.
abstract: Our previous study has demonstrated that tissue factor-factor VIIa (TF/FVIIa) complex promotes the proliferation and migration of colon cancer cell line SW620 through the activation of protease-activated receptor 2 (PAR2). In the current study, the underlying molecular mechanisms of TF/FVIIa/PAR2 signaling in SW620 cells were further explored, with the focus on the role of activator protein-1 (AP-1) subunit c-Jun. The results revealed that PAR2-AP and FVIIa could upregulate c-Jun expression and c-Jun phosphorylation in SW620 cells in a time-dependent manner. The effect of FVIIa was significantly blocked by anti-TF and anti-PAR2 antibodies. Protein kinase Cα (PKCα) inhibitor safingol and extracellular signal-regulated kinase 1 and 2 (ERK1/2) inhibitor U0126 abrogated the activation of c-Jun. In contrast, Ca(2+) chelators EGTA and thapsigargin, and p38MAPK inhibitor SB203580 had no effect. Suppression of c-Jun/AP-1 activation using a natural inhibitor curcumin decreased the expression of caspase-3, MMP-9, and TF, as well as the proliferation and migration of SW620 cells induced by PAR2-AP or FVIIa. Collectively, our findings suggest that c-Jun/AP-1 activation is required for TF/FVIIa/PAR2-induced SW620 cell proliferation and migration. PKCα and ERK1/2 are located upstream of c-Jun/AP-1 in this signaling pathway. Pharmacological inhibition of this pathway might be a novel strategy for colon cancer therapy.
authors.affiliation: Department of Cardiology, Affiliated Hospital of Jiangsu University, 438 Jiefang Road, Zhenjiang, Jiangsu, 212013, People's Republic of China.
authors.forename: Lichao
authors.initials: L
authors.lastname: Hu
authors.forename: Longfei
authors.initials: L
authors.lastname: Xia
authors.forename: Hong
authors.initials: H
authors.lastname: Zhou
authors.forename: Biao
authors.initials: B
authors.lastname: Wu
authors.forename: Yuan
authors.initials: Y
authors.lastname: Mu
authors.forename: Ying
authors.initials: Y
authors.lastname: Wu
authors.forename: Jinchuan
authors.initials: J
authors.lastname: Yan
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology; D002070:Butadienes / Q000494:pharmacology; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D002465:Cell Movement; D049109:Cell Proliferation; D003110:Colonic Neoplasms; D003474:Curcumin / Q000494:pharmacology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D015942:Factor VIIa / Q000502:physiology*; D006801:Humans; D020935:MAP Kinase Signaling System; D009570:Nitriles / Q000494:pharmacology; D051571:Protein Kinase C-alpha / Q000037:antagonists & inhibitors / Q000378:metabolism*; D016755:Proto-Oncogene Proteins c-jun / Q000378:metabolism; D044464:Receptor, PAR-2 / Q000378:metabolism*; D013110:Sphingosine / Q000031:analogs & derivatives / Q000494:pharmacology; D013925:Thromboplastin / Q000502:physiology*; D018808:Transcription Factor AP-1 / Q000037:antagonists & inhibitors / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D002070:Butadienes; D009570:Nitriles; D016755:Proto-Oncogene Proteins c-jun; D044464:Receptor, PAR-2; D018808:Transcription Factor AP-1; C113580:U 0126; D013925:Thromboplastin; C496628:PRKCA protein, human; D051571:Protein Kinase C-alpha; D048049:Extracellular Signal-Regulated MAP Kinases; D015942:Factor VIIa; D003474:Curcumin; D013110:Sphingosine; C005682:safingol