Abstract
AbstractCholesterol is an essential constituent of all mammalian cell membranes, and its availability is therefore a prerequisite for cellular growth and other functions. Several lines of evidence are now indicating an association between alterations of cholesterol homeostasis and cell cycle progression in cancer cells. However, the role of cholesterol in cell differentiation is still largely unknown. To begin to address this issue, in this study we examined changes in cholesterol metabolism and in the mRNA levels of proteins involved in cholesterol import and esterification (multi-drug resistance, MDR-3) and acylCoA:cholesterol acyltransferase (ACAT) and cholesterol export (caveolin-1) in Friend virus-induced erythroleukemia cells (MELC), in the absence or in the presence of the chemical inducer of differentiation, hexamethylene bisacetamide (HMBA). In uninduced MELC, cholesterol synthesis, esterification and MDR-3 and ACAT mRNAs increased as cells progressed from resting to proliferating phase, while caveolin-1 decreased. These results provide evidence that cholesterol esterification “per se” may have a role in cell division. When MELC are treated with HMBA, the reduction of DNA synthesis caused by the inducer is accompanied by an extensive decrease of cholesterol esterification and of ACAT and MDR-3 mRNA levels and by a significant increase in caveolin-1 mRNA. On the other hand, detection of cytoplasmic neutral lipids by staining MELC with oil-ORO, a dye able to evidence CE but not FC, revealed that HMBA-treatment inhibits cholesterol ester accumulation in MELC to approximately the same extent as the ACAT inhibitor, SaH. These results, other than, to add new insights on the possible role of cholesterol metabolism during tumor growth, for the first time indicate a possible involvement of cholesterol esterification pathways in the regulating of differentiation of erythroleukemic cells.
Highlights
Cholesterol balance in cells is a function of the amount taken up from extracellular sources, the amount newly made by the cell, the amount stored as cholesterol esters (CE) and the amount removed by cholesterol acceptors like high density lipoprotein (HDL)
polymerase chain reaction (PCR) analysis in murine erythroleukemia cell (MELC) and hexamethylene bisacetamide (HMBA)-cells To further evaluate the possibility that cholesterol esterification “per se” may be a limiting factor in determining cell growth and differentiation, we evaluated in MELC and HMBA-cells, the expression of some genes implicated in the regulation of intracellular cholesterol trafficking: acyl-CoA:cholesterol acyltransferase (ACAT)-1 and MDR-3, involved in the import of cholesterol, and caveolin-1, in the export
Intracellular cholesterol transport are receiving increasing attention as devices that cholesterol in specialized membrane platform called rafts could have a role in the regulation of a number of signal transduction pathways, including those involved in cell division and differentiation [31]
Summary
Cholesterol balance in cells is a function of the amount taken up from extracellular sources, the amount newly made by the cell, the amount stored as cholesterol esters (CE) and the amount removed by cholesterol acceptors like high density lipoprotein (HDL). In spite of the fact that MDR and caveolin-1 are recognized as playing a major role in intracellular cholesterol ester metabolism, it is still unclear why during tumor growth, membrane cholesterol is preferentially shifted to the ER, leading to an accumulation of CE, rather than being released to the appropriate extra cellular HDL acceptor. These observations prompted us to investigate levels of ACAT-1, MDR-3, and caveolin-1 mRNAs during differentiation of MELC induced by HMBA
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