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

Ender,Stephan  Albrecht; Dallmer,Andrea; Lässig,Florian; Lendeckel,Uwe; Wolke,Carmen

doi:10.3892/mmr.2014.2266

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

Authors:
- Stephan Albrecht Ender
- Andrea Dallmer
- Florian Lässig
- Uwe Lendeckel
- Carmen Wolke
View Affiliations

Affiliations: Department of Orthopaedics and Orthopaedic Surgery, University Medicine Greifswald, Sauerbruchstrasse, Greifswald D-17475, Germany, Institute of Medical Biochemistry and Molecular Biology, University Medicine Greifswald, Sauerbruchstrasse, Greifswald D-17475, Germany
Published online on: May 22, 2014 https://doi.org/10.3892/mmr.2014.2266
Pages: 804-810

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

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.

View Figures

View References

1	Peach MJ: Renin-angiotensin system: biochemistry and mechanisms of action. Physiol Rev. 57:313–370. 1977.PubMed/NCBI
2	Deshayes F and Nahmias C: Angiotensin receptors: a new role in cancer? Trends Endocrinol Metab. 16:293–299. 2005. View Article : Google Scholar : PubMed/NCBI
3	Tamarat R, Silvestre JS, Durie M and Levy BI: Angiotensin II angiogenic effect in vivo involves vascular endothelial growth factor- and inflammation-related pathways. Lab Invest. 82:747–756. 2002. View Article : Google Scholar : PubMed/NCBI
4	Pupilli C, Lasagni L, Romagnani P, Bellini F, Mannelli M, Misciglia N, Mavilia C, Vellei U, Villari D and Serio M: Angiotensin II stimulates the synthesis and secretion of vascular permeability factor/vascular endothelial growth factor in human mesangial cells. J Am Soc Nephrol. 10:245–255. 1999.PubMed/NCBI
5	Otani A, Takagi H, Oh H, Koyama S and Honda Y: Angiotensin II induces expression of the Tie2 receptor ligand, angiopoietin-2, in bovine retinal endothelial cells. Diabetes. 50:867–875. 2001. View Article : Google Scholar : PubMed/NCBI
6	Fujita M, Hayashi I, Yamashina S, Itoman M and Majima M: Blockade of angiotensin AT1a receptor signaling reduces tumor growth, angiogenesis, and metastasis. Biochem Biophys Res Commun. 294:441–447. 2002. View Article : Google Scholar : PubMed/NCBI
7	Suganuma T, Ino K, Shibata K, Kajiyama H, Nagasaka T, Mizutani S and Kikkawa F: Functional expression of the angiotensin II type 1 receptor in human ovarian carcinoma cells and its blockade therapy resulting in suppression of tumor invasion, angiogenesis, and peritoneal dissemination. Clin Cancer Res. 11:2686–2694. 2005. View Article : Google Scholar
8	Yasumatsu R, Nakashima T, Masuda M, Ito A, Kuratomi Y, Nakagawa T and Komune S: Effects of the angiotensin-I converting enzyme inhibitor perindopril on tumor growth and angiogenesis in head and neck squamous cell carcinoma cells. J Cancer Res Clin Oncol. 130:567–573. 2004. View Article : Google Scholar : PubMed/NCBI
9	Neo JH, Malcontenti-Wilson C, Muralidharan V and Christophi C: Effect of ACE inhibitors and angiotensin II receptor antagonists in a mouse model of colorectal cancer liver metastases. J Gastroenterol Hepatol. 22:577–584. 2007. View Article : Google Scholar : PubMed/NCBI
10	Ebert MP, Lendeckel U, Westphal S, Dierkes J, Glas J, Folwaczny C, Roessner A, Stolte M, Malfertheiner P and Röcken C: The angiotensin I-converting enzyme gene insertion/deletion polymorphism is linked to early gastric cancer. Cancer Epidemiol Biomarkers Prev. 14:2987–2389. 2005. View Article : Google Scholar : PubMed/NCBI
11	Röcken C, Lendeckel U, Dierkes J, Westphal S, Carl-McGrath S, Peters B, Krüger S, Malfertheiner P, Roessner A and Ebert MP: The number of lymph node metastases in gastric cancer correlates with the angiotensin I-converting enzyme gene insertion/deletion polymorphism. Clin Cancer Res. 11:2526–2530. 2005.PubMed/NCBI
12	Röcken C, Röhl FW, Diebler E, Lendeckel U, Pross M, Carl-McGrath S and Ebert MP: The angiotensin II/angiotensin II receptor system correlates with nodal spread in intestinal type gastric cancer. Cancer Epidemiol Biomarkers Prev. 16:1206–1212. 2007.PubMed/NCBI
13	Wasa J, Sugiura H, Kozawa E, Kohyama K, Yamada K and Taguchi O: The tumor suppressive effect of angiotensin II type 1 receptor antagonist in a murine osteosarcoma model. Anticancer Res. 31:123–127. 2011.PubMed/NCBI
14	Santos RA, Simoes e Silva AC, Maric C, Silva DM, Machado RP, de Buhr I, Heringer-Walther S, Pinheiro SV, Lopes MT, Bader M, Mendes EP, Lemos VS, Campagnole-Santos MJ, Schultheiss HP, Speth R and Walther T: Angiotensin-(1–7) is an endogenous ligand for the G protein-coupled receptor Mas. Proc Natl Acad Sci USA. 100:8258–8263. 2003.
15	Ni L, Feng Y, Wan H, Ma Q, Fan L, Qian Y, Li Q, Xiang Y and Gao B: Angiotensin-(1–7) inhibits the migration and invasion of A549 human lung adenocarcinoma cells through inactivation of the PI3K/Akt and MAPK signaling pathways. Oncol Rep. 27:783–790. 2012.
16	Gallagher PE and Tallant EA: Inhibition of human lung cancer cell growth by angiotensin-(1–7). Carcinogenesis. 25:2045–2052. 2004.
17	Feng Y, Ni L, Wan H, Fan L, Fei X, Ma Q, Gao B, Xiang Y, Che J and Li Q: Overexpression of ACE2 produces antitumor effects via inhibition of angiogenesis and tumor cell invasion in vivo and in vitro. Oncol Rep. 26:1157–1164. 2011.PubMed/NCBI
18	Qian YR, Guo Y, Wan HY, Fan L, Feng Y, Ni L, Xiang Y and Li QY: Angiotensin-converting enzyme 2 attenuates the metastasis of non-small cell lung cancer through inhibition of epithelial-mesenchymal transition. Oncol Rep. 29:2408–2414. 2013.PubMed/NCBI
19	Warburg O: On the origin of cancer cells. Science. 123:309–314. 1956. View Article : Google Scholar : PubMed/NCBI
20	Wu W and Zhao S: Metabolic changes in cancer: beyond the Warburg effect. Acta Biochim Biophys Sin (Shanghai). 45:18–26. 2013. View Article : Google Scholar : PubMed/NCBI
21	Cifuentes M, García MA, Arrabal PM, Martínez F, Yañez MJ, Jara N, Weil B, Domínguez D, Medina RA and Nualart F: Insulin regulates GLUT1-mediated glucose transport in MG-63 human osteosarcoma cells. J Cell Physiol. 226:1425–1432. 2011. View Article : Google Scholar : PubMed/NCBI
22	Costelloe CM, Macapinlac HA, Madewell JE, Fitzgerald NE, Mawlawi OR, Rohren EM, Raymond AK, Lewis VO, Anderson PM, Bassett RL Jr, Harrell RK and Marom EM: 18F-FDG PET/CT as an indicator of progression-free and overall survival in osteosarcoma. J Nucl Med. 50:340–347. 2009. View Article : Google Scholar : PubMed/NCBI
23	Franzius C, Bielack S, Flege S, Sciuk J, Jürgens H and Schober O: Prognostic significance of (18)F-FDG and (99m)Tc-methylene diphosphonate uptake in primary osteosarcoma. J Nucl Med. 43:1012–1017. 2002.PubMed/NCBI
24	Liu C, Lv XH, Li HX, Cao X, Zhang F, Wang L, Yu M and Yang JK: Angiotensin-(1–7) suppresses oxidative stress and improves glucose uptake via Mas receptor in adipocytes. Acta Diabetol. 49:291–299. 2012.
25	Giani JF, Mayer MA, Muñoz MC, Silberman EA, Höcht C, Taira CA, Gironacci MM, Turyn D and Dominici FP: Chronic infusion of angiotensin-(1–7) improves insulin resistance and hypertension induced by a high-fructose diet in rats. Am J Physiol Endocrinol Metab. 296:E262–E271. 2009.
26	Lever AF, Hole DJ, Gillis CR, McCallum IR, McInnes GT, MacKinnon PL, Meredith PA, Murray LS, Reid JL and Robertson JW: Do inhibitors of angiotensin-I-converting enzyme protect against risk of cancer? Lancet. 352:179–184. 1998. View Article : Google Scholar : PubMed/NCBI
27	Friis S, Sørensen HT, Mellemkjaer L, McLaughlin JK, Nielsen GL, Blot WJ and Olsen JH: Angiotensin-converting enzyme inhibitors and the risk of cancer: a population-based cohort study in Denmark. Cancer. 92:2462–2470. 2001. View Article : Google Scholar : PubMed/NCBI
28	Young D, Waitches G, Birchmeier C, Fasano O and Wigler M: Isolation and characterization of a new cellular oncogene encoding a protein with multiple potential transmembrane domains. Cell. 45:711–719. 1986. View Article : Google Scholar : PubMed/NCBI
29	Alenina N, Xu P, Rentzsch B, Patkin EL and Bader M: Genetically altered animal models for Mas and angiotensin-(1–7). Exp Physiol. 93:528–537. 2008.PubMed/NCBI
30	Hönicke A-S, Ender SA and Radons J: Combined administration of EGCG and IL-1 receptor antagonist efficiently downregulates IL-1-induced tumorigenic factors in U-2 OS human osteosarcoma cells. Int J Oncol. 41:753–758. 2012.
31	Chilukotia RK, Mostertz J, Bukowska A, Aderkast C, Felix SB, Busch M, Völker U, Goette A, Wolke C, Homuth G and Lendeckel U: Effects of irbesartan on gene expression revealed by transcriptome analysis of left atrial tissue in a porcine model of acute rapid pacing in vivo. Int J Cardiol. 168:2100–2108. 2013. View Article : Google Scholar : PubMed/NCBI