Melatonin Modulates the Microenvironment of Glioblastoma Multiforme by Targeting Sirtuin 1

Abstract

Natural products have historically been regarded as an important resource of therapeutic agents. Resveratrol and melatonin have been shown to increase SIRT1 activity and stimulate deacetylation. Glioblastoma multiforme (GBM) is the deadliest of malignant types of tumor in the central nervous system (CNS) and their biological features make treatment difficult. In the glioma microenvironment, infiltrating immune cells has been shown to possess beneficial effects for tumor progression. We analyzed SIRT1, CCL2, VCAM-1 and ICAM-1 in human glioma cell lines by immunoblotting. The correlation between those markers and clinico-pathological grade of glioma patients were assessed by the Gene Expression Omnibus (GEO) datasets analysis. We also used monocyte-binding assay to study the effects of melatonin on monocyte adhesion to GBM. Importantly, overexpression of SIRT1 by genetic modification or treatment of melatonin significantly downregulated the adhesion molecular VCAM-1 and ICAM-1 expression in GBM. CCL2-mediated monocyte adhesion and expression of VCAM-1 and ICAM-1 were regulated through SIRT1 signaling. SIRT1 is an important modulator of monocytes interaction with GBM that gives the possibility of improved therapies for GBM. Hence, this study provides a novel treatment strategy for the understanding of microenvironment changes in tumor progression.

Monocarboxylate Transporter 4 Regulates Glioblastoma Motility and Monocyte Binding Ability

“…The procedure of the monocyte-binding assay was described previously [76,77]. Briefly, human monocyte THP-1 cells were incubated with BCECF/AM (2 ,7 -bis-(2-carboxyethyl)-5-(and-6)carboxyfluorescein) and 0.1 µg fluorescent dye of in RPMI-1640 medium in an incubator for 1 h. GBM cells were treated with CHC or were transfected with short hairpin or wild-type MCT4 for the different time periods.…”

Clinical and Biological Significances of a Methyltransferase-Related Signature in Diffuse Glioma

“…On the one hand, SIRT1 knockdown significantly inhibited glioma cell proliferation, migration, invasion, promoted its apoptosis and potentiated TMZ toxicity (39)(40)(41). On the other hand, the expression of SIRT1 in GBM is significantly lower than normal brain tissue (42,43). Up-regulation of SIRT1 by genetic modification or treatment of melatonin significantly attenuated the adhesion molecular VCAM-1 and ICAM-1 expression in GBM, which modulated the monocytes interaction with GBM (43).…”

“…On the other hand, the expression of SIRT1 in GBM is significantly lower than normal brain tissue (42,43). Up-regulation of SIRT1 by genetic modification or treatment of melatonin significantly attenuated the adhesion molecular VCAM-1 and ICAM-1 expression in GBM, which modulated the monocytes interaction with GBM (43). SIRT1 activator SRT2183 suppresses glioma cell growth and destroyed neurospheres in vitro (44).…”

Melatonin’s Antineoplastic Potential Against Glioblastoma

“…The reduction of monocyte-related tumor-promotion effects in GBM could be a potentially useful antineoplastic strategy. With this in mind, Lai et al [73] reported that in vitro melatonin supplementation reduced monocyte adhesion molecules, as well as monocyte chemoattractant chemokine CCL2 expression in GBM, consequently attenuating monocyte recruitment and activity. Importantly, Lai et al [73] also observed that administration of melatonin increased the expression of sirtuin 1, which, in turn, reduced the expression of monocyte adhesion molecules.…”