title: RhoA/ROCK pathway mediates leptin-induced uPA expression to promote cell invasion in ovarian cancer cells.
abstract: Previous studies have shown that leptin, an adipocyte-secreted hormone, stimulates ovarian cancer invasion. Here, we investigated the contribution of uPA in leptin-induced ovarian cancer cell invasion. The cell invasion and migration experiments were carried out using matrigel invasion and wound healing assays in ovarian cancer cell lines (OVCAR3, SKOV3and CaoV-3). The mechanism underlying the invasive effect of leptin was examined using cell transfection with Ob-Rb siRNA, pre-treatment with a specific inhibitor of RhoA and ROCK, RhoA activation assay, OB-Rb, Rock and upA protein expression. Our results show that leptin induced ovarian cancer cell invasion via up-regulating upA in a time and dose-dependent manner, which was attenuated using knockdown of OB-Rb by siRNA. Moreover, pre-incubation with C3 (inhibitor of RhoA) and Y-27632 (inhibitor of ROCK) effectively attenuated leptin-induced upA expression and inhibited invasive ability of ovarian cancer cells. We also found that pretreatment with inhibitors of PI3K/AKT (LY294002), JAK/STAT (AG490) and NF-kB (BAY 11-7082) significantly reduced leptin-induced upA expression. Collectively, our findings demonstrate that OB-Rb, RhoA/ROCK, PI3K/AKT, JAK/STAT pathways and NF-kB activation are involved in leptin-induced upA expression. These results may provide a new mechanism that facilitates leptin-induced ovarian cancer invasion.
authors.affiliation: Department of Biochemistry and Bioinformatics Research Center, School of Pharmacy and Pharmaceutical Sciences, Isfahan University of Medical Sciences, Isfahan, Iran.
authors.forename: Ahmad
authors.initials: A
authors.lastname: Ghasemi
authors.affiliation: Surgical Oncology Research Center, Imam Reza Hospital, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran.
authors.forename: Seyed Isaac
authors.initials: SI
authors.lastname: Hashemy
authors.affiliation: Department of Biochemistry and Bioinformatics Research Center, School of Pharmacy and Pharmaceutical Sciences, Isfahan University of Medical Sciences, Isfahan, Iran.
authors.forename: Mahmoud
authors.initials: M
authors.lastname: Aghaei
authors.affiliation: Department of Biochemistry and Bioinformatics Research Center, School of Pharmacy and Pharmaceutical Sciences, Isfahan University of Medical Sciences, Isfahan, Iran. Electronic address: panjehpour@pharm.mui.ac.ir.
authors.forename: Mojtaba
authors.initials: M
authors.lastname: Panjehpour
mesh_terms: D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D005260:Female; D020868:Gene Silencing / Q000187:drug effects; D006801:Humans; D020738:Leptin / Q000494:pharmacology*; D016328:NF-kappa B / Q000378:metabolism; D009361:Neoplasm Invasiveness; D010051:Ovarian Neoplasms / Q000378:metabolism* / Q000473:pathology*; D010766:Phosphorylation / Q000187:drug effects; D054411:Receptors, Leptin / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D014568:Urokinase-Type Plasminogen Activator / Q000378:metabolism*; D054460:rho-Associated Kinases / Q000378:metabolism*; D020742:rhoA GTP-Binding Protein / Q000378:metabolism*
chemical_list: D020738:Leptin; D016328:NF-kappa B; D054411:Receptors, Leptin; D054460:rho-Associated Kinases; D014568:Urokinase-Type Plasminogen Activator; D020742:rhoA GTP-Binding Protein
keywords: Cell invasion; Leptin; Ovarian cancer; RhoA/rock pathway; Urokinase plasminogen activator