TY - JOUR
T1 - The Renin Angiotensin System (RAS) mediates bifunctional growth regulation in melanoma and is a novel target for therapeutic intervention
AU - Renziehausen, Alexander
AU - Wang, Hexiao
AU - Rao, Bhavya
AU - Weir, Lynda
AU - Nigro, Cristiana Lo
AU - Lattanzio, Laura
AU - Merlano, Marco
AU - Vega-Rioja, Antonio
AU - del Carmen Fernandez-Carranco, Maria
AU - Hajji, Nabil
AU - Matin, Rubeta
AU - Harwood, Catherine
AU - Li, Su
AU - Sim, Van Ren
AU - O’Neill, Kevin
AU - Evans, Alan
AU - Thompson, Alastair
AU - Szlosarek, Peter
AU - Fleming, Colin
AU - Stebbing, Justin
AU - Proby, Charlotte
AU - Tzakos, Andreas G.
AU - Syed, Nelofer
AU - Crook, Tim
N1 - Acknowledgements: The work was supported by The Chief Scientific Officer of Scotland, The Anonymous Trust, Tenovus Scotland (Dr Crook), Melanoma Focus (Professor Proby), The Leng Foundation (Professor Proby) and The Brain Tumour Research Campaign (Dr Syed). Antonio Vega-Rioja is under contract Proyectos I+D+I para jovenes investigadores from de Economica y Competitividad (SAF2014-60649-JN) and co-funded by Fondo Europeo de Regional-FEDER. Tim Crook is a Scottish Senior Clinical Fellow in Medical Oncology.
PY - 2019/3/28
Y1 - 2019/3/28
N2 - 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.
AB - 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.
KW - Melanoma
KW - Angiotensin
KW - Angiotensin receptor
KW - epigenetics
KW - Humans
KW - Amides/pharmacology
KW - Renin-Angiotensin System/drug effects
KW - Angiotensin II/pharmacology
KW - Neoplasm Metastasis
KW - Imidazoles/pharmacology
KW - Receptor, Angiotensin, Type 2/genetics
KW - Antihypertensive Agents/pharmacology
KW - Melanoma/genetics
KW - Molecular Targeted Therapy/methods
KW - Cell Proliferation/drug effects
KW - Cells, Cultured
KW - Angiotensin-Converting Enzyme Inhibitors/pharmacology
KW - Zebrafish
KW - Xenograft Model Antitumor Assays
KW - Animals
KW - DNA Methylation/drug effects
KW - Embryo, Nonmammalian
KW - Cell Line, Tumor
KW - Fumarates/pharmacology
KW - Pyridines/pharmacology
KW - Receptor, Angiotensin, Type 1/genetics
UR - http://www.scopus.com/inward/record.url?scp=85057309160&partnerID=8YFLogxK
U2 - 10.1038/s41388-018-0563-y
DO - 10.1038/s41388-018-0563-y
M3 - Article
C2 - 30478450
AN - SCOPUS:85057309160
SN - 0950-9232
VL - 38
SP - 2320
EP - 2336
JO - Oncogene
JF - Oncogene
ER -