Inhibition of cell growth by oxygenated derivatives of cholesterol

Chen, Harry W.; Kandutsch, Andrew A.; Waymouth, Charity

doi:10.1038/251419a0

Cited by 207 publications

(67 citation statements)

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“…4A). These results are similar to those previously observed when cultured cells were incubated with ethanolic 25-hydroxycholesterol or 7-ketocholesterol in the absence of exogenous cholesterol (7,9). On day 1, the medium was replaced with 2 ml of medium A containing one of the following additions: 0, none; A, native LDL (3.6 ug of protein per ml, 5.8 ,g of cholesterol per ml) or A, r-[25-HC oleate]LDL (3.6 jig of protein per ml, 0.72 ,ug of 25-hydroxycholesterol per ml).…”

Section: Resultssupporting

confidence: 81%

“…The rationale for the use of this molecule was based on the previous observation that oxygenated analogues of cholesterol, such as 7-ketocholesterol and 25-hydroxycholesterol, when added to cultured cells in an ethanolic solution, are potent suppressors of reductase activity (6)(7)(8). Suppression of reductase by oxygenated sterols prevents cells from synthesizing cholesterol and thus inhibits cellular growth unless the cells are provided with a source of exogenous cholesterol (7,9 purchased from New England Nuclear Corp. Tissue culture supplies and chemical reagents were obtained from previously described sources (4,7).…”

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confidence: 99%

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Receptor-mediated uptake of low density lipoprotein reconstituted with 25-hydroxycholesteryl oleate suppresses 3-hydroxy-3-methylglutaryl-coenzyme A reductase and inhibits growth of human fibroblasts

Krieger

Goldstein

Brown

1978

Proc. Natl. Acad. Sci. U.S.A.

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The free and esterified cholesterols of plasma low density lipoprotein (LDL) were extracted with heptane and replaced with 25-hydroxycholesteryl oleate. The resulting particle, designated r425-HC oleateJLDL, bound to LDL receptors on human fibroblasts, was taken up by adsorptive endocytosis and was hydrolyzed in lysosomes in a manner similar to that of native LDL. The r[25-HC oleateJLDL suppressed 3-hydroxy- Mammalian cells possess surface receptors that facilitate the uptake of specific macromolecules (1-3). Among the most extensively studied of these receptors is the one that binds the plasma cholesterol transport protein low density lipoprotein (LDL) (1). Once bound to its receptor, LDL is internalized by adsorptive endocytosis and delivered to lysosomes (1). The free cholesterol generated from the lysosomal hydrolysis of the cholesteryl esters of LDL satisfies the cholesterol needs of the cell and reduces cellular cholesterol synthesis by suppressing the activity of 3-hydroxy-3-methylglutaryl-coenzyme A reductase [mevalonate:NADP+ oxidoreductase (CoA-acylating), EC 1.1.1.34], the rate-controlling enzyme in the cholesterol biosynthetic pathway (1).Recently, a methol was developed for extracting the free and esterified cholesterdl of LDL with heptane and reconstituting the hydrophobic core of the lipoprotein with exogenous cholesteryl esters (4). The reconstituted LDL particle bound to the LDL receptor in human fibroblasts, after which it was taken up and delivered to lysosomes, supplying cholesterol to the cell.Unlike the free cholesterol on the surface of LDL, which exchanges readily with the cholesterol of cell membranes (5), the cholesteryl esters within the core of native or reconstituted LDL entered fibroblasts only when the entire lipoprotein was taken up through the receptor mechanism (4).These studies raised the possibility that LDL could be converted into a carrier that could selectively deliver a variety of hydrophobic substances to cells that possess LDL receptors. Moreover, if its core were reconstituted with a toxic hydrophobic molecule, LDL might be able to kill cells that possess LDL receptors, whereas cells that lack receptors would be resistant to this toxic effect. Such a toxic LDL preparation would be useful in vitro to select for cells carrying induced mutations in the LDL pathway.The current paper reports the synthesis of a toxic LDL preparation reconstituted with 25-hydroxycholesteryl oleate. The rationale for the use of this molecule was based on the previous observation that oxygenated analogues of cholesterol, such as 7-ketocholesterol and 25-hydroxycholesterol, when added to cultured cells in an ethanolic solution, are potent suppressors of reductase activity (6-8). Suppression of reductase by oxygenated sterols prevents cells from synthesizing cholesterol and thus inhibits cellular growth unless the cells are provided with a source of exogenous cholesterol (7,9 The publication costs of this article were defrayed in part by page charge payment. This article must therefore be...

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Section: Resultssupporting

confidence: 81%

mentioning

confidence: 99%

Receptor-mediated uptake of low density lipoprotein reconstituted with 25-hydroxycholesteryl oleate suppresses 3-hydroxy-3-methylglutaryl-coenzyme A reductase and inhibits growth of human fibroblasts

Krieger

Goldstein

Brown

1978

Proc. Natl. Acad. Sci. U.S.A.

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“…Daniel Cirera-Salinas, 1,2, † Montse pauta, 1,3, † Ryan M. Allen, 4 Alessandro G. Salerno, 1 Cristina M. Ramírez, 1 Aránzazu Chamorro-Jorganes, 1 Amarylis C. Wanschel, 1 Miguel A. Lasunción, 5 Manuel Morales-Ruiz, 3 Yajaira Suárez, 1 Ángel Baldán, 4 enric esplugues 2,6 and Carlos Fernández-Hernando 1A, bottom part). Notably, endogenous inhibition of miR-33 using anti-miR-33 oligonucleotides (2.5 fold decrease) increases mRNA expression of CDK6 and ABCA1 in both cell lines (Fig.…”

Section: Mir-33 Regulates Cell Proliferation and Cell Cycle Progressionmentioning

confidence: 99%

“…1 As an essential component of mammalian cell membranes, cells require cholesterol for proliferation. [2][3][4][5] In addition to its structural requirement, cholesterol is important for other cell functions, such as bile acid and hormone synthesis as well as during embryonic development. The requirement of cholesterol for cell growth and division of mammalian cells has been known for many years, [2][3][4] but whether this is just a consequence of its use for membrane formation or whether it also plays a regulatory role in this process has not been clarified.…”

Section: Introductionmentioning

confidence: 99%

Mir-33 regulates cell proliferation and cell cycle progression

et al. 2012

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“…Thus, in HSL +/+ Supplemental Material can be found at: ( 4,36 ). The absence of CEH activity in HSL Ϫ / Ϫ mouse testis may induce a decrease in the hydrolysis of CE that causes a reduction in the availability of free cholesterol, which is involved in cell proliferation ( 48,49 ) and, therefore, in spermatogenesis. The aim of the present work was to study the SR-B cellular expression in HSL Ϫ / Ϫ mouse testis for their potential importance in cholesterol provision, as well as their localization to lipid rafts and the activity of related signaling cascades, which ultimately may be involved in infertility in HSL Ϫ / Ϫ male mice.…”

Section: ) Mouse Testismentioning

confidence: 99%

HSL-knockout mouse testis exhibits class B scavenger receptor upregulation and disrupted lipid raft microdomains

Casado

Huerta

Ortiz

et al. 2012

Journal of Lipid Research

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This article is available online at http://www.jlr.org Supplementary key words hormone-sensitive lipase • cholesterol esters • steroidogenesis • spermatogenesis • fertility • sterility Spermatogenesis occurs in a series of proliferative and differentiation stages, which can be subdivided into mitotic, meiotic, and spermatogenic phases. Each phase is characterized by distinct cell types (spermatogonia, spermatocytes, and spermatids, respectively) ( 1, 2 ). Pathologic, experimental, and natural seasonal arrest of spermatogenesis are all associated with increases in lipid droplets ( 3, 4 ), indicating a close relationship between fertility and changes in lipid metabolism during spermatogenesis ( 5 ). A constant supply of cholesterol is required within Leydig cells to serve as precursor for the synthesis of steroid hormones (steroidogenesis) ( 6, 7 ), whereas in the seminiferous tubules, cholesterol is involved in germinal cell differentiation to spermatozoids (spermatogenesis or gametogenesis) ( 8 ).There is also considerable evidence indicating that cholesterol is required for the development of gametes and fertility in both sexes. Disruption of the DHCR24 gene, which encodes the cholesterol biosynthetic enzyme desmosterol reductase, causes infertility in male mice ( 9 ). In addition to cholesterol, sterol Abstract There is a tight relationship between fertility and changes in cholesterol metabolism during spermatogenesis. In the testis, class B scavenger receptors (SR-B) SR-BI, SR-BII, and LIMP II mediate the selective uptake of cholesterol esters from HDL, which are hydrolyzed to unesterifi ed cholesterol by hormone-sensitive lipase (HSL). HSL is critical

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Inhibition of cell growth by oxygenated derivatives of cholesterol

Cited by 207 publications

References 14 publications

Receptor-mediated uptake of low density lipoprotein reconstituted with 25-hydroxycholesteryl oleate suppresses 3-hydroxy-3-methylglutaryl-coenzyme A reductase and inhibits growth of human fibroblasts

Receptor-mediated uptake of low density lipoprotein reconstituted with 25-hydroxycholesteryl oleate suppresses 3-hydroxy-3-methylglutaryl-coenzyme A reductase and inhibits growth of human fibroblasts

Mir-33 regulates cell proliferation and cell cycle progression

HSL-knockout mouse testis exhibits class B scavenger receptor upregulation and disrupted lipid raft microdomains

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