Propranolol Inhibits the Proliferation of Human Glioblastoma Cell Lines through Notch1 and Hes1 Signaling System

Abstract

The anti-tumor effect of the beta-adrenergic receptor antagonist propranolol in breast cancer is well known; however, its activity in glioblastoma is not well-evaluated. The Notch-Hes pathway is known to regulate cell differentiation, proliferation, and apoptosis. We investigated the effect of propranolol to human glioblastoma cell lines, and the role of Notch and Hes signaling in this process. Methods : We performed immunohistochemical staining on 31 surgically resected primary human glioblastoma tissues. We also used glioblastoma cell lines of U87-MG, LN229, and neuroblastoma cell line of SH-SY5Y in this study. The effect of propranolol and isoproterenol on cell proliferation was evaluated using the MTT assay (absorbance 570 nm). The impact of propranolol on gene expression (Notch and Hes) was evaluated using real-time polymerase chain reaction (RT-PCR, whereas protein levels of Notch1 and Hes1 were measured using Western blotting (WB), simultaneously. Small interfering RNA (siRNA) was used to suppress the Notch gene to investigate its role in the proliferation of glioblastoma. Results : Propranolol and isoproterenol caused a dose-dependent decrease in cell proliferation (MTT assay). RT-PCR showed an increase in Notch1 and Hes1 expression by propranolol, whereas WB demonstrated increase in Notch1 protein, but a decrease in Hes1 by propranolol. The proliferation of U87-MG and LN229 was not significantly suppressed after transfection with Notch siRNA. Conclusion :These results demonstrated that propranolol suppressed the proliferation of glioblastoma cell lines and neuroblastoma cell line, and Hes1 was more closely involved than Notch1 was in glioblastoma proliferation.

Propranolol: A “Pick and Roll” Team Player in Benign Tumors and Cancer Therapies

“…Furthermore, several in vitro and in vivo studies described the antitumor properties (viability, oxidative stress, or metabolic and immunity restoration) of propranolol in different carcinomas, including breast [ 23 ], colon [ 24 ], gastric [ 25 ], glioblastoma [ 26 ], lung [ 17 , 27 , 28 ], nasopharyngeal [ 29 ], ovarian [ 30 , 31 ], and pancreatic [ 25 , 32 , 33 , 34 ].…”

Intracranial tumors elicit systemic sympathetic hyperactivity that limits immunotherapeutic responses

“…Importantly, our studies highlight the impact of β-adrenergic blockade on local and systemic immune responses, and not directly on tumor cells. Several studies have examined the direct in vitro inhibitive effects of propranolol on glioma cell lines 83–86 , although our data reveal relatively low expression of β-adrenergic receptors on tumor cells compared to the immune compartment. Likewise, there is only a single study investigating the translational relevance of glioma adrenergic receptor expression.…”

A Novel Localization in Human Large Extracellular Vesicles for the EGF-CFC Founder Member CRIPTO and Its Biological and Therapeutic Implications

“…CRIPTO is able to interact with a plethora of molecules on the cell membrane, activating different signaling pathways and cellular responses [ 17 , 64 ]. The U87 cells contain most of the surface molecules to whom CRIPTO binds; in fact, they expose on the membrane the main CRIPTO interactors that are ALK4 and ALK7 receptors, being able to activate in the U87 the downstream Smad signaling pathway [ 72 ], Glypican 1 [ 73 ], as well as the Wnt co-receptors low-density lipoprotein receptor-related protein LRPs [ 74 ], Notch1 [ 75 ], and GRP78 [ 76 ]. It would be tempting to speculate that the lEV-associated CRIPTO protein might act as a dominant negative able to bind and sequester in an inactive form the target receptor complexes on the U87 cell surface, thus altering the downstream cellular response.…”