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The renin angiotensin system (RAS) mediates bifunctional growth regulation in melanoma and is a novel target for therapeutic intervention

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Názov: The renin angiotensin system (RAS) mediates bifunctional growth regulation in melanoma and is a novel target for therapeutic intervention
Autori: 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
Zdroj: RISalud-ANDALUCIA. Repositorio Institucional de Salud de Andalucía
instname
Informácie o vydavateľovi: Springer Science and Business Media LLC, 2018.
Rok vydania: 2018
Predmety: 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
Popis: 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.
Druh dokumentu: Article
Popis súboru: application/pdf
Jazyk: English
ISSN: 1476-5594
0950-9232
DOI: 10.1038/s41388-018-0563-y
Prístupová URL adresa: 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
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  Data: The renin angiotensin system (RAS) mediates bifunctional growth regulation in melanoma and is a novel target for therapeutic intervention
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– Name: Abstract
  Label: Description
  Group: Ab
  Data: 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.
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  Data: 10.1038/s41388-018-0563-y
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      – TitleFull: The renin angiotensin system (RAS) mediates bifunctional growth regulation in melanoma and is a novel target for therapeutic intervention
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            NameFull: Laura Lattanzio
      – PersonEntity:
          Name:
            NameFull: Marco Merlano
      – PersonEntity:
          Name:
            NameFull: Antonio Vega-Rioja
      – PersonEntity:
          Name:
            NameFull: Maria del Carmen Fernandez-Carranco
      – PersonEntity:
          Name:
            NameFull: Nabil Hajji
      – PersonEntity:
          Name:
            NameFull: Rubeta Matin
      – PersonEntity:
          Name:
            NameFull: Catherine Harwood
      – PersonEntity:
          Name:
            NameFull: Su Li
      – PersonEntity:
          Name:
            NameFull: Van Ren Sim
      – PersonEntity:
          Name:
            NameFull: Kevin O’Neill
      – PersonEntity:
          Name:
            NameFull: Alan Evans
      – PersonEntity:
          Name:
            NameFull: Alastair Thompson
      – PersonEntity:
          Name:
            NameFull: Peter Szlosarek
      – PersonEntity:
          Name:
            NameFull: Colin Fleming
      – PersonEntity:
          Name:
            NameFull: Justin Stebbing
      – PersonEntity:
          Name:
            NameFull: Charlotte Proby
      – PersonEntity:
          Name:
            NameFull: Andreas G. Tzakos
      – PersonEntity:
          Name:
            NameFull: Nelofer Syed
      – PersonEntity:
          Name:
            NameFull: Tim Crook
    IsPartOfRelationships:
      – BibEntity:
          Dates:
            – D: 26
              M: 11
              Type: published
              Y: 2018
          Identifiers:
            – Type: issn-print
              Value: 14765594
            – Type: issn-print
              Value: 09509232
            – Type: issn-locals
              Value: edsair
            – Type: issn-locals
              Value: edsairFT
          Numbering:
            – Type: volume
              Value: 38
          Titles:
            – TitleFull: Oncogene
              Type: main
ResultId 1