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

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

Synthetic Cathinones—Prevalence and Motivations for Use

This book chapter reviews the prevalence and motivations for use of synthetic cathinones with respect to their availability, legal status, numbers and seized amounts

Chemogenetic inhibition of IST1-CHMP1B interaction impairs endosomal recycling and promotes unconventional LC3 lipidation at stalled endosomes

Abstract The Endosomal Sorting Complex Required for Transport (ESCRT) machinery constitutes a multisubunit protein complex that plays an essential role in membrane remodeling and trafficking. ESCRTs regulate a wide array of cellular processes, encompassing cytokinetic abscission, cargo sorting into multivesicular bodies (MVBs), membrane repair and autophagy. Given the versatile functionality of ESCRTs and the intricate organizational structure of the ESCRT complex, the targeted modulation of distinct ESCRT-mediated membrane deformations for functional dissection poses a considerable challenge. This study presents a pseudo-natural product targeting IST1-CHMP1B within the ESCRT-III complex. This compound specifically disrupts the interaction between IST1 and CHMP1B, thereby inhibiting the formation of IST1-CHMP1B copolymers essential for normal-topology membrane scission events. While the compound has no impact on cytokinesis, MVB sorting and exosome biogenesis, it rapidly hinders transferrin receptor (TfR) recycling in cells, resulting in the accumulation of transferrin in perinuclear endosomal recycling tubules. Stalled recycling endosomes acquire unconventional LC3 lipidation, establishing a link between non-canonical LC3 lipidation and endosomal recycling