title: Angiotensin Converting Enzyme Regulates Cell Proliferation and Migration.
abstract: BACKGROUND
  The angiotensin-I converting enzyme (ACE) plays a central role in the renin-angiotensin system, acting by converting the hormone angiotensin-I to the active peptide angiotensin-II (Ang-II). More recently, ACE was shown to act as a receptor for Ang-II, and its expression level was demonstrated to be higher in melanoma cells compared to their normal counterparts. However, the function that ACE plays as an Ang-II receptor in melanoma cells has not been defined yet.
  
  
  OBJECTIVE
  Therefore, our aim was to examine the role of ACE in tumor cell proliferation and migration.
  
  
  RESULTS
  We found that upon binding to ACE, Ang-II internalizes with a faster onset compared to the binding of Ang-II to its classical AT1 receptor. We also found that the complex Ang-II/ACE translocates to the nucleus, through a clathrin-mediated process, triggering a transient nuclear Ca2+ signal. In silico studies revealed a possible interaction site between ACE and phospholipase C (PLC), and experimental results in CHO cells, demonstrated that the β3 isoform of PLC is the one involved in the Ca2+ signals induced by Ang-II/ACE interaction. Further studies in melanoma cells (TM-5) showed that Ang-II induced cell proliferation through ACE activation, an event that could be inhibited either by ACE inhibitor (Lisinopril) or by the silencing of ACE. In addition, we found that stimulation of ACE by Ang-II caused the melanoma cells to migrate, at least in part due to decreased vinculin expression, a focal adhesion structural protein.
  
  
  CONCLUSIONS
  ACE activation regulates melanoma cell proliferation and migration.
authors.affiliation: Department of Physiology and Biophysics, Federal University of Minas Gerais, Belo Horizonte, MG, Brazil.|Department of Natural Sciences, Federal University of São João del Rei, São João Del Rey, MG, Brazil.
authors.forename: Erika Costa de
authors.initials: EC
authors.lastname: Alvarenga
authors.affiliation: Department of Physiology and Biophysics, Federal University of Minas Gerais, Belo Horizonte, MG, Brazil.
authors.forename: Matheus de Castro
authors.initials: MC
authors.lastname: Fonseca
authors.affiliation: Department of Physiology and Biophysics, Federal University of Minas Gerais, Belo Horizonte, MG, Brazil.
authors.forename: Clarissa Coelho
authors.initials: CC
authors.lastname: Carvalho
authors.affiliation: Department of Physiology and Biophysics, Federal University of Minas Gerais, Belo Horizonte, MG, Brazil.
authors.forename: Rodrigo Machado
authors.initials: RM
authors.lastname: Florentino
authors.affiliation: Department of Physiology and Biophysics, Federal University of Minas Gerais, Belo Horizonte, MG, Brazil.
authors.forename: Andressa
authors.initials: A
authors.lastname: França
authors.affiliation: Department of Physics, Federal University of Ceará, Fortaleza, CE, Brazil.
authors.forename: Eveline
authors.initials: E
authors.lastname: Matias
authors.affiliation: Department of Biophysics, Federal University of São Paulo, São Paulo, SP, Brazil.
authors.forename: Paola Bianchi
authors.initials: PB
authors.lastname: Guimarães
authors.affiliation: Department of Biophysics, Federal University of São Paulo, São Paulo, SP, Brazil.
authors.forename: Carolina
authors.initials: C
authors.lastname: Batista
authors.affiliation: Department of Physics, Federal University of Ceará, Fortaleza, CE, Brazil.
authors.forename: Valder
authors.initials: V
authors.lastname: Freire
authors.affiliation: Department of Biophysics, Federal University of São Paulo, São Paulo, SP, Brazil.
authors.forename: Adriana Karaoglanovic
authors.initials: AK
authors.lastname: Carmona
authors.affiliation: Department of Biophysics, Federal University of São Paulo, São Paulo, SP, Brazil.
authors.forename: João Bosco
authors.initials: JB
authors.lastname: Pesquero
authors.affiliation: Department of Physics, Federal University of Minas Gerais, Belo Horizonte, MG, Brazil.
authors.forename: Ana Maria
authors.initials: AM
authors.lastname: de Paula
authors.affiliation: Department of Physiology and Biophysics, Federal University of Minas Gerais, Belo Horizonte, MG, Brazil.|Department of Morphology, Federal University of Minas Gerais, Belo Horizonte, MG, Brazil.
authors.forename: Giselle
authors.initials: G
authors.lastname: Foureaux
authors.affiliation: Department of Physiology and Biophysics, Federal University of Minas Gerais, Belo Horizonte, MG, Brazil.
authors.forename: Maria de Fatima
authors.initials: MF
authors.lastname: Leite
mesh_terms: D000804:Angiotensin II / Q000378:metabolism*; D000818:Animals; D016466:CHO Cells; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D002467:Cell Nucleus / Q000378:metabolism*; D049109:Cell Proliferation / Q000187:drug effects; D003198:Computer Simulation; D003412:Cricetulus; D006801:Humans; D017706:Lisinopril / Q000494:pharmacology; D008545:Melanoma / Q000201:enzymology* / Q000235:genetics / Q000378:metabolism; D007703:Peptidyl-Dipeptidase A / Q000235:genetics / Q000378:metabolism*; D054799:Phospholipase C beta / Q000378:metabolism*; D021381:Protein Transport; D016596:Vinculin / Q000378:metabolism*
chemical_list: C488955:VCL protein, human; D000804:Angiotensin II; D016596:Vinculin; D017706:Lisinopril; D054799:Phospholipase C beta; C488034:ACE protein, human; D007703:Peptidyl-Dipeptidase A