The Renin Angiotensin System (RAS) mediates bifunctional growth regulation in melanoma and is a novel target for therapeutic intervention

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 StebbingCharlotte Proby, Andreas G. Tzakos, Nelofer Syed, Tim Crook

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    Abstract

    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 knock-down 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.
    Original languageEnglish
    Pages (from-to)2320-2336
    Number of pages17
    JournalOncogene
    Volume38
    Early online date26 Nov 2018
    DOIs
    Publication statusPublished - 28 Mar 2019

    Keywords

    • Melanoma
    • Angiotensin
    • Angiotensin receptor
    • epigenetics
    • Humans
    • Amides/pharmacology
    • Renin-Angiotensin System/drug effects
    • Angiotensin II/pharmacology
    • Neoplasm Metastasis
    • Imidazoles/pharmacology
    • Receptor, Angiotensin, Type 2/genetics
    • Antihypertensive Agents/pharmacology
    • Melanoma/genetics
    • Molecular Targeted Therapy/methods
    • Cell Proliferation/drug effects
    • Cells, Cultured
    • Angiotensin-Converting Enzyme Inhibitors/pharmacology
    • Zebrafish
    • Xenograft Model Antitumor Assays
    • Animals
    • DNA Methylation/drug effects
    • Embryo, Nonmammalian
    • Cell Line, Tumor
    • Fumarates/pharmacology
    • Pyridines/pharmacology
    • Receptor, Angiotensin, Type 1/genetics

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    Cite this

    Renziehausen, A., Wang, H., Rao, B., Weir, L., Nigro, C. L., Lattanzio, L., Merlano, M., Vega-Rioja, A., del Carmen Fernandez-Carranco, M., Hajji, N., Matin, R., Harwood, C., Li, S., Sim, V. R., O’Neill, K., Evans, A., Thompson, A., Szlosarek, P., Fleming, C., ... Crook, T. (2019). The Renin Angiotensin System (RAS) mediates bifunctional growth regulation in melanoma and is a novel target for therapeutic intervention. Oncogene, 38, 2320-2336. https://doi.org/10.1038/s41388-018-0563-y