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Angiotensin Converting Enzyme Regulates Cell Proliferation and Migration

2016; Public Library of Science; Volume: 11; Issue: 12 Linguagem: Inglês

10.1371/journal.pone.0165371

1932-6203

Érika Costa de Alvarenga, Matheus de Castro Fonseca, Clarissa Coelho Carvalho, Rodrigo M. Florentino, Andressa França, Eveline M. Bezerra, Paola Bianchi Guimarães, Carolina Batista, V. N. Freire, Adriana K. Carmona, João Bosco Pesquero, Ana Paula, Giselle Foureaux, Maria de Fátima Leite,

Computational Drug Discovery Methods

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. Aim 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. Conclusion ACE activation regulates melanoma cell proliferation and migration.