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.
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 beta 3 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.
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