Expression and function of the ACE2/angiotensin(1–7)/Mas axis in osteosarcoma cell lines U-2 OS and MNNG-HOS

Abstract

The renin-angiotensin-system (RAS), via its classical angiotensin-converting enzyme (ACE)/angiotensin II/angiotensin II type 1 receptor (AT1R)-axis, is associated with proliferation and metastasis of numerous types of solid tumor. AT1R blockers reduce tumor volume and decrease liver and lung metastasis in murine models of osteosarcoma. Expression and function of the alternative ACE2/Ang(1-7)/Mas axis in osteosarcoma is yet to be studied. In the present study, the basic and interleukin (IL)-1β-stimulated expression of components of this alternative RAS axis were analyzed and the impact of Mas on proliferation and/or migration of U-2 OS and MNNG-HOS osteosarcoma cells was studied. Quantitative polymerase chain reaction revealed that the two cell lines expressed the Ang(1‑7)-generating peptidases ACE2, neutral endopeptidase 24.11 and prolyl-endopeptidase together with the putative receptor for Ang(1-7), Mas. IL-1β provoked an induction of Mas mRNA and protein expression which was associated with a reduction of proliferation and migration. By contrast, small interfering RNA-mediated knockdown of Mas expression led to increased cell proliferation. In conclusion, osteosarcoma cells express a functional active alternative ACE2/Ang(1-7)/Mas axis. The induction and reinforcement of this axis may be beneficial for the treatment of osteosarcoma by reducing growth and preventing cancer metastasis. These effects may be achieved directly by the administration of Mas agonists or, indirectly, via blocking the classical AngII RAS axis via ACE inhibitors or AT1R antagonists.

ACE2 overexpression inhibits acquired platinum resistance-induced tumor angiogenesis in NSCLC

“…Current evidence supports the idea that both host and tumor RAS are important for tumor growth and angiogenesis in cancer (10,15). As a new part of RAS, the ACE2/Ang-(1-7)/Mas axis also plays an important role in cancer (16,17). Recent studies have shown that low ACE2 expression may be a useful indicator of poor prognosis in HCC and gallbladder cancer (18,19).…”

Angiotensin II Type 1 Receptor Knockdown Impairs Interleukin‐1β‐Induced Cytokines in Human Periodontal Fibroblasts

“…In another study, IL-1b was able to increase Mas receptor expression and ACE-2 in a concentration-dependent manner in osteosarcoma cells. 36 Use of AT1R antagonist (losartan) did not interfere with IL-1b-induced mRNA for AT1R or other investigated RAS components (Mas receptor, ACE and ACE-2 enzymes) in both fibroblast subtypes. Initially, concentrations of 10 mM were used for losartan as pretreatment.…”

“…In the present study, it is interesting to point out that IL‐1β stimulation also increased mRNA expression for Mas receptor and ACE, in addition to AT1R in control HPLF in experiments of negative control of gene silencing (data not shown). In another study, IL‐1β was able to increase Mas receptor expression and ACE‐2 in a concentration‐dependent manner in osteosarcoma cells 36 …”

The ACE2/Angiotensin-(1–7)/Mas Receptor Axis: Pleiotropic Roles in Cancer

“…Ender et al (2014) discovered that the knockdown of Mas expression mediated by small interfering RNA leads to increased cell proliferation in osteosarcoma and suggested that targeting the ACE2/Ang-(1–7)/Mas axis may be beneficial for the treatment of osteosarcoma by reducing cancer cell proliferation and preventing cancer metastasis (Figure 2). …”