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.
Highlights
SIRT1 known as sirtuin 1, is one of the sirtuin family that belongs to class III histone deacetylases (HDACs) and show different functions and structure [1]
The U251 and U87 Glioblastoma multiforme (GBM) cell lines were grown in minimum essential medium (MEM), The A172 and ALTS1C1 glioma cell lines were grown in Dulbecco’s modified eagle medium (DMEM), and human monocyte cell line THP-1 was grown in RPMI-1640 medium
The gene expression of SIRT1, ICAM-1 and VCAM-1 values were obtained from the GSE4290 dataset and we evaluated the correlation with human glioma pathological grade
Summary
SIRT1 known as sirtuin 1, is one of the sirtuin family that belongs to class III histone deacetylases (HDACs) and show different functions and structure [1]. In the glioma microenvironment, infiltrating immune cells have demonstrated to possess beneficial effects for tumor progression [38,39]. Recent studies have shown that the crosstalk between infiltration immune cells and tumor cells is mediated by various soluble factors [41]. A recent study reported that reducing the effects of the monocyte of tumor-promotion in GBM can be a potential strategy for therapies [43]. It has been shown that the CCL2 expression level correlates with the recruitment of monocytes/macrophages into tumor tissues [48]. This study indicated that melatonin reduced the ICAM-1, VCAM-1 as well as chemokine CCL2 expression in GBM. We suggested that SIRT1 plays a critical role between monocytes and GBM interaction. It might help identify novel targets and improved therapies for GBM
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