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Originally published In Press as doi:10.1194/jlr.M400407-JLR200 on February 1, 2005

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Journal of Lipid Research, Vol. 46, 920-929, May 2005
Copyright © 2005 by American Society for Biochemistry and Molecular Biology

Effects of distal cholesterol biosynthesis inhibitors on cell proliferation and cell cycle progression

Carlos Fernández*, Miguel Martín*, Diego Gómez-Coronado* and Miguel A. Lasunción1,*,{dagger}

* Servicio de Bioquímica-Investigación, Hospital Ramón y Cajal, 28034 Madrid, Spain
{dagger} Departamento de Bioquímica y Biología Molecular, Universidad de Alcalá, 28771 Alcalá de Henares, Spain

1 To whom correspondence should be addressed. e-mail: miguel.a.lasuncion{at}hrc.es

Cholesterol is a major lipid component of the plasma membrane in animal cells. In addition to its structural requirement, cholesterol is essential in cell proliferation and other cell processes. The aim of the present study was to elucidate the stringency of the requirement for cholesterol as a regulator of proliferation and cell cycle progression, compared with other sterols of the cholesterol biosynthesis pathway. Human promyelocytic HL-60 cells were cultured in cholesterol-free medium and treated with different distal inhibitors of cholesterol biosynthesis (zaragozic acid, SKF 104976, SR 31747, BM 15766, and AY 9944), which allow the synthesis of isoprenoid derivatives and different sets of sterol intermediates, but not cholesterol.

The results showed that only the inhibition of sterol {Delta}7-reductase was compatible with cell proliferation. Blocking cholesterol biosynthesis upstream of this enzyme resulted in the inhibition of cell proliferation and cell cycle arrest selectively in G2/M phase.

Supplementary key words sterols • 7-dehydrocholesterol • HL-60


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