Angiotensin II type 2 receptor signalling promotes glioblastoma growth: A novel target for therapeutic intervention

Abstract

The renin-angiotensin system (RAS) is a major homeostatic regulator of salt-water equilibrium, intravascular volume and blood pressure. Aside from its importance in normal physiology, locally expressed components of this system are increasingly being implicated in numerous diverse pathologies, including cancer. However, the role of angiotensin signalling and its potential for therapeutic intervention remain largely unexplored in glioblastoma (GBM). This study set out to investigate the functions of the angiotensin II type 1 and type 2 receptors (AT1R and AT2R) in GBM and determine whether clinically approved drugs that target these receptors could be repurposed as novel therapeutics. To this end several GBM cell lines, patient derived primary cell cultures and stem-like cells (GSCs) were profiled for angiotensin receptor gene expression and interrogated in functional assays using angiotensin II or receptor-specific antagonists. This is the first report that inhibition of AT2R significantly reduces GBM cell growth, migration and the ability of these cells to induce angiogenesis under serum-starved conditions. This was particularly evident when GBM cells expressing this receptor were treated with the AT2R antagonist EMA401, which is currently under clinical development for the treatment of neuropathic pain. RNA-sequencing studies revealed that blocking AT2R leads to significant differential expression of numerous genes linked to pathways important in cancer, particularly upregulation of putative tumour suppressor genes such as RPH3AL or DUSP2 and downregulation of genes known to enhance tumour cell survival such as TRPV6 or ALDH3A1. Contrary to previous reports in other cancer types, inhibition of AT1R had no direct effect on the growth of GBM cells, despite significantly limiting their ability to induce angiogensis in vitro. Together these findings demonstrate that AT2R is the main angiotensin receptor supporting GBM growth and that its inhibition is a novel therapeutic strategy that warrants pre-clinical testing.