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

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 saltwater 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.

The role of the renin‐angiotensin system in skin physiology and pathophysiology

“…CpG islands are regions of the genome, which are in close proximity to the promoter and regulate its activity; methylation of CpG islands leads to promoter inactivation. [69] However, even though this study provided a whole set of data, which consistently supported the authors' conclusions, the more common notion on the role of angiotensin receptors in cancer in the scientific literature is that the AT 1 R acts pro-proliferative, while the AT 2 R is a tumor suppressor that inhibits proliferation, migration and metastasis. [72,73] In fact, another very recent study by Martinez-Meza et al [71] reported that selective stimulation or overexpression of AT 2 Rs in mouse B16/F10 and human A375 melanoma cells reduced "normal" and transendothelial migration.…”

“…The B16/ F10 mouse melanoma cell line is an exception and possesses only AT 2 Rs. [68][69][70][71] Normal melanocytes express exclusively AT 1 Rs. [2,69]…”

Antihypertensives and melanoma: An updated review

“…These medications are most commonly used for the treatment of hypertension, acute myocardial infarction, heart failure, and diabetic nephropathy. However, ACEIs and ARBs have also been considered as potential anti-tumor agents given the possible role of angiotensin II in melanoma progression (Renziehausen et al, 2019). Furthermore, both ACEIs and…”

Single Peptide Backbone Surrogate Mutations to Regulate Angiotensin GPCR Subtype Selectivity

“…The AT 1 Ri sr esponsible for cell proliferation, angiogenesis, oxidative stress, and cardiovascular dysfunctions, whereas the AT 2 R has been reported to counteracts everal of the effectsm ediated by the AT 1 R, conferring cardio-protection, [2] antiproliferation,a ntiinflammation, and neuroregeneration. [3] Recently, we identified that AT 2 Rc an provide therapeutic opportunities in melanomas, [4] human pancreatic ductal adenocarcinoma, [5] and breast cancer. [6] In addition, we showed that AGTR 1 CpG island methylation in serum could serve as a novel biomarker of metastaticm elanoma.…”

“…[6] In addition, we showed that AGTR 1 CpG island methylation in serum could serve as a novel biomarker of metastaticm elanoma. [4] These discoveries were feasible owing to the establishmento fo ur selectivec ompound, [Y] 6 -Angiotensin II, for the AT 2 R. [6] Witha ni ncreasing body of evidence indicating that selectivet argeting of AT 2 R can provide ab etter treatment for many different diseases, [7] there is an imminentn eed to further develop angiotensin receptor subtype-selective ligands.…”