Modulation of Cholesterol Homeostasis by Antiproliferative Drugs in Human Pterygium Fibroblasts

Peiretti, Enrico; Dessı̀, Sandra; Mulas, Claudia; Abete, Claudia; Norfo, Claudia; Putzolu, M.; Fossarello, Maurizio

doi:10.1167/iovs.06-1054

Cited by 22 publications

(22 citation statements)

References 59 publications

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“…We moreover demonstrated that cholesterol esterification in smooth muscle cells is a key event in vascular proliferative diseases [20]. Furthermore, inhibition of CEs synthesis partially blocked cell proliferation, although the extent of the latter effect was dependent on the cell type [20][21][22][23], suggesting the potential involvement of cholesterol esterification as a new pathway implicated in cell growth. On the other hand, several studies have demonstrated how proliferation of tumour cells is arrested in a delipidated medium, with inhibition being almost completely prevented following addition of LDL and/or HDL [24,25].…”

Section: Introductionmentioning

confidence: 81%

A lipoprotein source of cholesteryl esters is essential for proliferation of CEM-CCRF lymphoblastic cell line

et al. 2011

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Tumour are characterised by a high content of cholesteryl esters (CEs) stored in lipid droplets purported to be due to a high rate of intracellular esterification of cholesterol. To verify whether and which pathways involved in CE accumulation are essential in tumour proliferation, the effect of CE deprivation, from both exogenous and endogenous sources, on CEM-CCRF cells was investigated. Cholesterol synthesis, esterification and content, low-density lipoprotein (LDL) binding and high-density lipoprotein (HDL)-CE uptake were evaluated in cultured in both conventional and delipidated bovine serum with or without oleic or linoleic acids, cholesteryl oleate, LDL and HDL. High content of CEs in lipid droplets in this cell line was due to esterification of both newly synthesised cholesterol and that obtained from hydrolysis of LDL; moreover, a significant amount of CE was derived from HDL-CE uptake. Cell proliferation was slightly affected by either acute or chronic treatment up to 400 μM with Sz-58035, an acyl-cholesteryl cholesterol esterification inhibitor (ACAT); although when the enzyme activity was continuously inhibited, CE content in lipid droplets was significantly higher than those in control cells. In these cells, analysis of intracellular and medium CEs revealed a profile reflecting the characteristics of bovine serum, suggesting a plasma origin of CE molecules. Cell proliferation arrest in delipidated medium was almost completely prevented in the first 72 h by LDL or HDL, although in subsequent cultures with LDL, it manifested an increasing mortality rate. This study suggests that high content of CEs in CEM-CCRF is mainly derived from plasma lipoproteins and that part of CEs stored in lipid droplets are obtained after being taken up from HDL. This route appears to be up-regulated according to cell requirements and involved in low levels of c-HDL during cancer. Moreover, the dependence of tumour cells on a source of lipoprotein provides a novel impetus in developing therapeutic strategies for use in the treatment of some tumours.

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Section: Introductionmentioning

confidence: 81%

A lipoprotein source of cholesteryl esters is essential for proliferation of CEM-CCRF lymphoblastic cell line

et al. 2011

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“…37 Everolimus and pioglitazone, drugs that alter the metabolism of cholesterol, have been shown to decrease pterygia fibroblasts proliferation, as well as the levels of molecules involved in the regulating intracellular cholesterol homeostasis acyl-coenzyme A cholesterol acyltransferase and multidrug resistance protein. 39 The results of these studies suggest the use of topical drugs in the prevention of pterygium proliferation by the modulation of cholesterol ester metabolism.…”

Section: Alterations In Cholesterol Metabolismmentioning

confidence: 94%

“…[8][9][10] Alternatively, a wide array of pathogenic factors has been proposed, including viral infections, 11 epigenetic aberrations, 12-14 epithelialmesenchymal transition, 15,16 immunologic [17][18][19][20] and anti-apoptotic mechanisms, 21-24 angiogenic 2,25,26 and lymphangiogenic stimulation, 27,28 deregulation of extracellular matrix modulators 4,29 and growth factors, 30 inflammation cascades, 31-33 recruitment of bone-marrow-derived stem and progenitor cells, [34][35][36] and modifications in cholesterol metabolism. [37][38][39] However, most of these factors are more related to the development and maintenance of the disease than to its origin. It has been shown that some of these factors are directly or indirectly related to UV radiation exposure, as will be discussed further.…”

Section: Introductionmentioning

confidence: 99%

Molecular Basis of Pterygium Development

Cárdenas-Cantú

Zavala

Valenzuela

et al. 2014

Seminars in Ophthalmology

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Pterygium pathogenesis is mainly related to UV light exposure. However, the exact mechanisms by which it is formed have not been elucidated. Clinical advances in surgical treatment use conjunctival autografts and amniotic membranes in combination with adjuvant therapies, including mitomycin C, β-radiation, and 5-fluoroacil, to reduce recurrence. Several studies aim to unveil the molecular mechanisms underlying pterygium growth and proliferation. They demonstrate the role of different factors, such as viruses, oxidative stress, DNA methylation, apoptotic and oncogenic proteins, loss of heterozygosity, microsatellite instability, inflammatory mediators, extracellular matrix modulators, lymphangiogenesis, cell epithelial-mesenchymal transition, and alterations in cholesterol metabolism in pterygium development. Understanding the molecular basis of pterygium provides new potential therapeutic targets for its prevention and elimination. This review focuses on providing a broad overview of what is currently known regarding molecular mechanisms of pterygium pathogenesis.

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“…We and others have proposed that accumulation of CE spares energy needed for de novo sterol synthesis, allowing greater proliferation and migration and perhaps a quicker return to growth after a period of stasis (Batetta, Pani et al 1999;Antalis, Arnold et al 2010;Antalis, Uchida et al 2011). The process of cholesterol esterification was linked to proliferation in multiple studies in different cancer cell lines (Batetta, Pani et al 1999;Peiretti, Dessi et al 2007;Paillasse, de Medina et al 2009;Antalis, Arnold et al 2010;Mulas, Abete et al 2011), implying a complex network of signaling pathways and gene expression that ties cholesterol accretion to tumorigenesis. However, the exact role of CE in tumorigenesis remains to be determined.…”

Section: Experimental and Mechanistic Evidence For Role Of Ldl In Cancermentioning

confidence: 99%

Lipoproteins and Cancer

Antalis¹,

Buhman²

2012

Lipoproteins - Role in Health and Diseases

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Modulation of Cholesterol Homeostasis by Antiproliferative Drugs in Human Pterygium Fibroblasts

Cited by 22 publications

References 59 publications

A lipoprotein source of cholesteryl esters is essential for proliferation of CEM-CCRF lymphoblastic cell line

A lipoprotein source of cholesteryl esters is essential for proliferation of CEM-CCRF lymphoblastic cell line

Molecular Basis of Pterygium Development

Lipoproteins and Cancer

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