Cholesterol is essential for mitosis progression and its deficiency induces polyploid cell formation.
As an essential component of mammalian cell membranes, cells require cholesterol for proliferation, which is either obtained from plasma lipoproteins or synthesized intracellularly from acetyl-CoA. In addition to cholesterol, other non-sterol mevalonate derivatives are necessary for DNA synthesis, such as the phosphorylated forms of isopentane, farnesol, geranylgeraniol, and dolichol. The aim of the present study was to elucidate the role of cholesterol in mitosis. For this, human leukemia cells (HL-60) were incubated in a cholesterol-free medium and treated with SKF 104976, which inhibits cholesterol biosynthesis by blocking sterol 14alpha-demethylase, and the expression of relevant cyclins in the different phases of the cell cycle was analyzed by flow cytometry. Prolonged cholesterol starvation induced the inhibition of cytokinesis and the formation of polyploid cells, which were multinucleated and had mitotic aberrations. Supplementing the medium with cholesterol completely abolished these effects, demonstrating they were specifically due to cholesterol deficiency. This is the first evidence that cholesterol is essential for mitosis completion and that, in the absence of cholesterol, the cells fail to undergo cytokinesis, entered G1 phase at higher DNA ploidy (tetraploidy), and then progressed through S (rereplication) into G2, generating polyploid cells.
Fernández
Carlos
C
Servicio de Bioquímica-Investigación, Hospital Ramón y Cajal, Madrid, Spain.
Lobo Md
María del Val T
Mdel V
Gómez-Coronado
Diego
D
Lasunción
Miguel A
MA
D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D016203:CDC2 Protein Kinase / Q000037:antagonists & inhibitors / Q000378:metabolism; D002467:Cell Nucleus / Q000235:genetics / Q000378:metabolism / Q000648:ultrastructure; D002784:Cholesterol / Q000172:deficiency / Q000494:pharmacology / Q000502:physiology*; D002869:Chromosome Aberrations / Q000187:drug effects; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D016193:G1 Phase / Q000187:drug effects / Q000235:genetics; D016195:G2 Phase / Q000187:drug effects / Q000235:genetics; D015726:Giant Cells / Q000187:drug effects / Q000378:metabolism / Q000648:ultrastructure; D018922:HL-60 Cells; D006801:Humans; D007810:Lanosterol / Q000031:analogs & derivatives* / Q000494:pharmacology; D046529:Microscopy, Electron, Transmission; D008938:Mitosis / Q000187:drug effects / Q000502:physiology*; D010088:Oxidoreductases / Q000037:antagonists & inhibitors / Q000378:metabolism; D011123:Polyploidy; D016196:S Phase / Q000187:drug effects / Q000235:genetics; D058886:Sterol 14-Demethylase
C548418:CYP51A1 protein, human; D065607:Cytochrome P-450 Enzyme Inhibitors; D004791:Enzyme Inhibitors; C071375:SK&F 104976; D007810:Lanosterol; D003577:Cytochrome P-450 Enzyme System; D002784:Cholesterol; D010088:Oxidoreductases; D058886:Sterol 14-Demethylase; D016203:CDC2 Protein Kinase