The renin angiotensin system (RAS) mediates bifunctional growth regulation in melanoma and is a novel target for therapeutic intervention
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| Title: | The renin angiotensin system (RAS) mediates bifunctional growth regulation in melanoma and is a novel target for therapeutic intervention |
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| Authors: | Alexander Renziehausen, Hexiao Wang, Bhavya Rao, Lynda Weir, Cristiana Lo Nigro, Laura Lattanzio, Marco Merlano, Antonio Vega-Rioja, Maria del Carmen Fernandez-Carranco, Nabil Hajji, Rubeta Matin, Catherine Harwood, Su Li, Van Ren Sim, Kevin O’Neill, Alan Evans, Alastair Thompson, Peter Szlosarek, Colin Fleming, Justin Stebbing, Charlotte Proby, Andreas G. Tzakos, Nelofer Syed, Tim Crook |
| Source: | RISalud-ANDALUCIA. Repositorio Institucional de Salud de Andalucía instname |
| Publisher Information: | Springer Science and Business Media LLC, 2018. |
| Publication Year: | 2018 |
| Subject Terms: | Type 2/genetics, 0301 basic medicine, Embryo, Nonmammalian, Pyridines, name=Cancer Research, Angiotensin-Converting Enzyme Inhibitors, Angiotensin receptor, Cell Proliferation/drug effects, Renin-Angiotensin System, Angiotensin, Fumarates, Fumarates/pharmacology, Molecular Targeted Therapy, Neoplasm Metastasis, Melanoma, Zebrafish, Cells, Cultured, Imidazoles/pharmacology, Pyridines/pharmacology, 0303 health sciences, Cultured, Nonmammalian, Tumor, Angiotensin II, Imidazoles, Antihypertensive Agents/pharmacology, DNA Methylation/drug effects, 3. Good health, Embryo, Receptor, Cells, name=Genetics, Angiotensin-Converting Enzyme Inhibitors/pharmacology, Receptor, Angiotensin, Type 2, Receptor, Angiotensin, Type 1, Cell Line, Melanoma/genetics, 03 medical and health sciences, Cell Line, Tumor, Animals, Humans, Antihypertensive Agents, Amides/pharmacology, Cell Proliferation, epigenetics, name=Molecular Biology, DNA Methylation, Xenograft Model Antitumor Assays, Amides, Renin-Angiotensin System/drug effects, Angiotensin II/pharmacology, Molecular Targeted Therapy/methods, Type 1/genetics |
| Description: | Despite emergence of new systemic therapies, metastatic melanoma remains a challenging and often fatal form of skin cancer. The renin-angiotensin system (RAS) is a major physiological regulatory pathway controlling salt-water equilibrium, intravascular volume and blood pressure. Biological effects of the RAS are mediated by the vasoactive hormone angiotensin II (AngII) via two receptor subtypes, AT1R (encoded by AGTR1) and AT2R (encoded by AGTR2). We report decreasing expression and increasing CpG island methylation of AGTR1 in metastatic versus primary melanoma and detection in serum of methylated genomic DNA from the AGTR1 CpG island in metastatic melanoma implying that AGTR1 encodes a tumour suppressor function in melanoma. Consistent with this hypothesis, antagonism of AT1R using losartan or shRNA-mediated knockdown in melanoma cell lines expressing AGTR1 resulted in acquisition of the ability to proliferate in serum-free conditions. Conversely, ectopic expression of AGTR1 in cell lines lacking endogenous expression inhibits proliferation irrespective of the presence of AngII implying a ligand-independent suppressor function for AT1R. Treatment of melanoma cell lines expressing endogenous AT2R with either AngII or the AT2R-selective agonist Y6AII induces proliferation in serum-free conditions whereas the AT2R-specific antagonists PD123319 and EMA401 inhibit melanoma growth and angiogenesis and potentiate inhibitors of BRAF and MEK in cells with BRAF V600 mutations. Our results demonstrate that the RAS has both oncogenic and tumour suppressor functions in melanoma. Pharmacological inhibition of AT2R may provide therapeutic opportunities in melanomas expressing this receptor and AGTR1 CpG island methylation in serum may serve as a novel biomarker of metastatic melanoma. |
| Document Type: | Article |
| File Description: | application/pdf |
| Language: | English |
| ISSN: | 1476-5594 0950-9232 |
| DOI: | 10.1038/s41388-018-0563-y |
| Access URL: | https://discovery.dundee.ac.uk/ws/files/29557175/Author_Accepted_Manuscript.pdf https://pubmed.ncbi.nlm.nih.gov/30478450 http://hdl.handle.net/10668/13242 https://discovery.dundee.ac.uk/ws/files/29557175/Author_Accepted_Manuscript.pdf https://www.ncbi.nlm.nih.gov/pubmed/30478450 https://pubmed.ncbi.nlm.nih.gov/30478450/ https://www.nature.com/articles/s41388-018-0563-y https://europepmc.org/article/MED/30478450 https://mdanderson.elsevierpure.com/en/publications/the-renin-angiotensin-system-ras-mediates-bifunctional-growth-reg https://hdl.handle.net/10668/13242 |
| Rights: | Springer TDM |
| Accession Number: | edsair.doi.dedup.....d1876b0b1f9ba73775c7e2425f9f2c4c |
| Database: | OpenAIRE |
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