Novel Insights into the Antagonistic Effects of Losartan against Angiotensin II/AGTR1 Signaling in Glioblastoma Cells

SIMPLE SUMMARY: Patients with high-grade glioma (HGG) such as glioblastoma (GBM) who undergo surgical resection with adjuvant therapy have a mean overall survival of 14.6 months and 100% of recurrence. Thus, these disappointing outcomes in terms of glioblastoma life expectancy require seeking novel pharmacological tools, including drug repurposing. In the present study, we identify a novel molecular mechanism through which Losartan antagonizes Angiotensin II (Ang II)/Angiotensin II type I receptor (AGTR1) signaling, overexpressed in GBM cells. For instance, we demonstrate how Losartan drastically inhibits the stimulatory effects of Ang II on aromatase activity and consequently reduces local estrogen production, sustaining cancer progression. Thus, it is reasonable to repurpose Losartan as an adjuvant pharmacological tool to be implemented prospectively in the novel therapeutic strategies adopted in GBM patients. ABSTRACT: New avenues for glioblastoma therapy are required due to the limited mortality benefit of the current treatments. The renin-angiotensin system (RAS) exhibits local actions and works as a paracrine system in different tissues and tumors, including glioma. The glioblastoma cell lines U-87 MG and T98G overexpresses Angiotensin II (Ang II)/Angiotensin II type I receptor (AGTR1) signaling, which enhances in vitro and in vivo local estrogen production through a direct up-regulation of the aromatase gene promoters p I.f and p I.4. In addition, Ang II/AGTR1 signaling transactivates estrogen receptor-α in a ligand-independent manner through mitogen-activated protein kinase (MAPK) activation. The higher aromatase mRNA expression in patients with glioblastoma was associated with the worst survival prognostic, according to The Cancer Genome Atlas (TCGA). An intrinsic immunosuppressive glioblastoma tumor milieu has been previously documented. We demonstrate how Ang II treatment in glioblastoma cells increases programmed death-ligand 1 (PD-L1) expression reversed by combined exposure to Losartan (LOS) in vitro and in vivo. Our findings highlight how LOS, in addition, antagonizes the previously documented neoangiogenetic, profibrotic, and immunosuppressive effects of Ang II and drastically inhibits its stimulatory effects on local estrogen production, sustaining glioblastoma cell growth. Thus, Losartan may represent an adjuvant pharmacological tool to be repurposed prospectively for glioblastoma treatment.