Dataset Information

Regulated Hyaluronan Synthesis by Vascular Cells.

ABSTRACT: Cellular microenvironment plays a critical role in several pathologies including atherosclerosis. Hyaluronan (HA) content often reflects the progression of this disease in promoting vessel thickening and cell migration. HA synthesis is regulated by several factors, including the phosphorylation of HA synthase 2 (HAS2) and other covalent modifications including ubiquitination and O-GlcNAcylation. Substrate availability is important in HA synthesis control. Specific drugs reducing the UDP precursors are able to reduce HA synthesis whereas the hexosamine biosynthetic pathway (HBP) increases the concentration of HA precursor UDP-N-acetylglucosamine (UDP-GlcNAc) leading to an increase of HA synthesis. The flux through the HBP in the regulation of HA biosynthesis in human aortic vascular smooth muscle cells (VSMCs) was reported as a critical aspect. In fact, inhibiting O-GlcNAcylation reduced HA production whereas increased O-GlcNAcylation augmented HA secretion. Additionally, O-GlcNAcylation regulates HAS2 gene expression resulting in accumulation of its mRNA after induction of O-GlcNAcylation with glucosamine treatments. The oxidized LDLs, the most common molecules related to atherosclerosis outcome and progression, are also able to induce a strong HA synthesis when they are in contact with vascular cells. In this review, we present recent described mechanisms involved in HA synthesis regulation and their role in atherosclerosis outcome and development.

SUBMITTER: Viola M

PROVIDER: S-EPMC4581571 | biostudies-other | 2015

REPOSITORIES: biostudies-other

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Regulated Hyaluronan Synthesis by Vascular Cells.

Viola Manuela M Karousou Evgenia E D'Angelo Maria Luisa ML Caon Ilaria I De Luca Giancarlo G Passi Alberto A Vigetti Davide D

International journal of cell biology 20150910

Cellular microenvironment plays a critical role in several pathologies including atherosclerosis. Hyaluronan (HA) content often reflects the progression of this disease in promoting vessel thickening and cell migration. HA synthesis is regulated by several factors, including the phosphorylation of HA synthase 2 (HAS2) and other covalent modifications including ubiquitination and O-GlcNAcylation. Substrate availability is important in HA synthesis control. Specific drugs reducing the UDP precurso ...[more]

PMID: 26448750

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Project description:The vitamin D receptor (VDR) and its ligand 1,25(OH)2D3 (1,25D) exert anti-tumor effects, but considerable heterogeneity has been reported in different model systems. In general, cell lines derived from aggressive tumor subtypes such as Triple Negative Breast Cancer (TNBC) express low levels of VDR and are less sensitive to 1,25D than those derived from more differentiated tumor types. We have previously reported that 1,25D inhibits hyaluronic acid synthase 2 (HAS2) expression and hyaluronic acid (HA) synthesis in murine TNBC cells. Here we confirmed the inhibitory effect of 1,25D on HA synthesis in human Hs578T cells representative of the mesenchymal/stem-like (MSL) subtype of TNBC. Because HA synthesis requires the production of hexoses for incorporation into HA, we predicted that the high HA production characteristic of Hs578T cells would require sustained metabolic changes through the hexosamine biosynthetic pathway (HBP). We thus examined metabolic gene expression in Hs578T cell variants sorted for High (HAHigh) and Low (HALow) HA production, and the ability of 1,25D to reverse these adaptive changes. HAHigh populations exhibited elevated HA production, smaller size, increased proliferation and higher motility than HALow populations. Despite their more aggressive phenotype, HAHigh populations retained expression of VDR protein at levels comparable to that of parental Hs578T cells and HALow subclones. Treatment with 1,25D decreased production of HA in both HAHigh and HALow populations. We also found that multiple metabolic enzymes were aberrantly expressed in HAHigh cells, especially those involved in glutamine and glucose metabolism. Notably, Glutaminase (GLS), a known oncogene for breast cancer, was strongly upregulated in HAHigh vs. HALow cells and its expression was significantly reduced by 1,25D (100 nM, 24 h). Consistent with this finding, Seahorse extracellular flux analysis indicated that respiration in HAHigh cells was significantly more dependent on exogenous glutamine than HALow cells, however, acute 1,25D exposure did not alter metabolic flux. In contrast to GLS, the glutamate transporter SLC1A7 was significantly reduced in HAHigh cells compared to HALow cells and its expression was enhanced by 1,25D. These findings support the concept that 1,25D can reverse the metabolic gene expression changes associated with HA production in cancer cells with aggressive phenotypes.

Dataset Information

Regulated Hyaluronan Synthesis by Vascular Cells.

Publications

Regulated Hyaluronan Synthesis by Vascular Cells.

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