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

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          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.

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          Author and article information

          Journal
          Cancers (Basel)
          Cancers
          MDPI AG
          2072-6694
          2072-6694
          Sep 10 2021
          : 13
          : 18
          Affiliations
          [1 ] Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, 87036 Rende, CS, Italy.
          [2 ] Centro Sanitario, University of Calabria, 87036 Rende, CS, Italy.
          [3 ] Department of Bioinformatics, Semmelweis University, 1094 Budapest, Hungary.
          [4 ] Cancer Biomarker Research Group, Research Centre for Natural Sciences, 1117 Budapest, Hungary.
          Article
          cancers13184555
          10.3390/cancers13184555
          8469998
          34572782
          dc111bdd-c69d-44e8-8a17-cb0d1c22a882
          History

          Angiotensin II,Angiotensin II type I receptor,Losartan,aromatase,estrogen,glioblastoma,renin-angiotensin system

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