Essential role for mevalonate synthesis in DNA replication

Quesney-Huneeus, V; Wiley, Millie Hughes; Siperstein, Marvin D.

doi:10.1073/pnas.76.10.5056

Cited by 262 publications

(130 citation statements)

References 26 publications

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“…We have shown, however, that mevalonate at concentrations as high as 1 mM has no effect on the proliferation of human umbilical vein endothelial cells or their ability to form tubules in Matrigel. 2 Furthermore, medium conditioned with mevalonate-pretreated MDA-MB-435 cells also had no effect on the proliferation of human umbilical vein endothelial cells in culture and, indeed, inhibited the formation of tubules by these cells in Matrigel. 2 These observations suggest that mevalonate does not promote the growth of tumors by enhancing their ability to neovascularize and may even inhibit this process.…”

Section: Fig 4 Mevalonate Increases Cdk-2 Activitymentioning

confidence: 99%

“…As might be expected, these effects are the converse of cell cycle events that follow mevalonate depletion in cultured cells treated with statins (2). It has been known for some time that a critical level of mevalonate or an as yet unidentified nonsterol metabolite of mevalonate is required for initiation of DNA synthesis (2). Inadequate intracellular levels of mevalonate prevent entry of cells into S phase, resulting in a characteristic G 1 phase growth arrest (2, 38).…”

Section: Fig 2 Mevalonate Promotes the Growth Of Mda-mb-435 Human Cmentioning

confidence: 99%

“…In addition to being a precursor of cholesterol, mevalonate is required for a number of cellular processes including DNA synthesis and proliferation (2). Mevalonate is also the precursor of non-sterol isoprenoids that have a variety of functions including prenylation of growth-regulating proteins and oncoproteins (3,4).…”

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confidence: 99%

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Mevalonate Promotes the Growth of Tumors Derived from Human Cancer Cells in Vivo and Stimulates Proliferation in Vitro with Enhanced Cyclin-dependent Kinase-2 Activity

Duncan¹,

El-Sohemy²,

Archer

2004

Journal of Biological Chemistry

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Malignant cells are known to have elevated rates of mevalonate synthesis because of increased levels and catalytic efficiency of 3-hydroxy-3-methylglutaryl-CoA reductase. Whether this increased mevalonate synthesis occurs as a consequence of increased requirements for a mevalonate-derived metabolite in response to rapid growth or whether mevalonate promotes the growth of tumor cells is unknown. To address this question, we administered mevalonate via miniosmotic pumps to nude mice inoculated with MDA-MB-435 human cancer cells. After 13 weeks of growth, tumors in mevalonatetreated mice were significantly larger than tumors in saline-treated, control mice (1.52 ؎ 0.26 g versus 0.81 ؎ 0.27 g respectively, p < 0.05). The cancer cells treated in culture with mevalonate also demonstrated increased proliferation rates associated with accelerated entry of cells into S phase. These cells had enhanced total and cyclin A-immunoprecipitable cyclin-dependent kinase-2 (CDK-2) activity, increased activating phosphorylation of CDK-2, and decreased inhibitory binding of CDK-2 to p21 Cip1 . Our findings demonstrate that mevalonate promotes tumor growth and suggest that an increase in mevalonate synthesis in extrahepatic tissues following cholesterol-lowering therapy may explain the elevated risk of cancer shown in some studies.HMG-CoA 1 reductase is the rate-limiting enzyme in cholesterol biosynthesis that catalyzes the formation of mevalonate (1). In addition to being a precursor of cholesterol, mevalonate is required for a number of cellular processes including DNA synthesis and proliferation (2). Mevalonate is also the precursor of non-sterol isoprenoids that have a variety of functions including prenylation of growth-regulating proteins and oncoproteins (3, 4). Elevated mevalonate synthesis has been reported in malignant breast (5), lung (6), leukemia and lymphoma (7), and hepatoma cells (8). Whether increased mevalonate synthesis occurs in malignant cells simply as a consequence of increased requirements for a mevalonate-derived metabolite in response to rapid growth or whether mevalonate promotes the growth of tumor cells is unknown.HMG-CoA reductase is regulated through a multivalent feedback mechanism that is controlled, in part, by intracellular cholesterol levels (1). Cells meet their cholesterol requirements by de novo synthesis or by uptake from plasma of cholesterolrich low density lipoprotein. A fall in circulating levels of low density lipoprotein causes a decrease in its uptake, and the resultant drop in intracellular cholesterol levels leads to a compensatory stimulation of mevalonate synthesis through upregulation of HMG-CoA reductase (1). We have shown that a diet rich in cholesterol that raised circulating cholesterol levels also significantly decreased mammary gland HMG-CoA reductase activity (5) and inhibited the development of chemically induced mammary tumors in rats (5, 9). We have also shown in mice that a diet rich in cholesterol protects against the development of chemically induced preneoplastic lesio...

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Section: Fig 4 Mevalonate Increases Cdk-2 Activitymentioning

confidence: 99%

Section: Fig 2 Mevalonate Promotes the Growth Of Mda-mb-435 Human Cmentioning

confidence: 99%

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Mevalonate Promotes the Growth of Tumors Derived from Human Cancer Cells in Vivo and Stimulates Proliferation in Vitro with Enhanced Cyclin-dependent Kinase-2 Activity

Duncan¹,

El-Sohemy²,

Archer

2004

Journal of Biological Chemistry

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“…We have recently shown that lovastatin disrupts early signaling events such as tyrosine phosphorylation levels of the PDGF receptor and its association with PI-3-kinase (McGuire et al, 1993). Moreover, lovastatin arrests cultured cells predominantly in the G 1 phase of the cell cycle and produces a characteristic rounded morphology (Quesney-Huneeus et al, 1979;Sinensky and Logel, 1985;Fenton et al, 1992). Lovastatin has also been found to inhibit tumor growth of cells expressing oncogenic H-Ras in nude mice, but at doses that blocked tumor growth, lovastatin was extremely toxic and some animals died (Sebti et al, 1991).…”

Section: Introductionmentioning

confidence: 99%

Geranylgeraniol potentiates lovastatin inhibition of oncogenic H-Ras processing and signaling while preventing cytotoxicity

McGuire

Sebti

1997

Oncogene

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Oncogenic H-Ras requires farnesylation for its transforming activity. Lovastatin inhibits both protein farnesylation and geranylgeranylation by decreasing cellular pools of farnesylpyrophosphate (FPP) and geranylgeranylpyrophosphate (GGPP), respectively. Use of lovastatin as a chemotherapeutic agent has been precluded by its signi®cant cytotoxic e ects. In this report, we describe a novel approach utilizing a combination of lovastatin and geranylgeraniol (GGOH) to potentiate the ability of lovastatin to block oncogenic H-Ras signaling and concomitantly rescue lovastatin toxicity. GGOH co-treatment with lovastatin enhances inhibition of oncogenic H-Ras processing and constitutive activation of mitogen-activated protein kinase (MAPK), and preserves the processing of geranylgeranyltransferase (GGTase) I and GGTase II protein substrates. Moreover, co-treatment with GGOH signi®cantly (15-fold) attenuates the cytotoxic e ects of lovastatin as well as prevents lovastatin-induced cell rounding. These results demonstrate that GGOH potentiates the antioncogenic/anti-signaling activity of lovastatin while antagonizing its cytotoxicity. These opposing e ects are due to a GGOH metabolite that serves simultaneously as a potent inhibitor for farneslyltransferase as well as a substrate for GGTases I and II.

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“…DEHP is lipophilic and can suppress the activity of HMG CoA reductase (3-hydroxy-3-methylglutaryl CoA reductase, EC 1.1.1.34) which is the enzyme responsible for the regulation of de novo cholesterogenesis (23). This action could provide one mechanism by which DEHP might suppress cell growth since intermediates from the synthesis of cholesterol appear to be required for cell division (24,25). We are currently studying another group of membrane-bound enzymes which appear to be affected by DEHP.…”

Section: Resultsmentioning

confidence: 99%

Concentration-dependent inhibition of development of GGT positive foci in rat liver by the environmental contaminant di(2-ethylhexyl) phthalate.

DeAngelo¹,

Queral²,

Garrett³

1985

Environ Health Perspect

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The ability of di(2-ethylhexyl) phthalate (DEHP), a widely used plasticizer and environmental contaminant, to suppress development of putative preneoplastic lesions in rat liver was evaluated. y-Glutamyl transpeptidase-positive (GGT + ) foci were initiated in the livers of Sprague-Dawley male rats with a single dose of diethylnitrosamine (DEN) following partial hepatectomy. Promotion of foci was commenced by feeding a choline-deficient diet (CD). A group of control rats was fed a choline-supplemented diet (CS). The ability of DEHP to suppress the emergence of GGT + foci was evaluated by feeding additional groups of rats the CD diet containing either 0.1%, 0.5%, 1.0% or 2.0% DEHP. The CD diet promoted the number of GGT+ foci above levels in control livers. Inclusion of the plasticizer to the levels of 0.5%, 1.0% and 2.0% in the CD diet effectively inhibited the appearance of the foci. However, DEHP was unable to inhibit the promoting effect of the CD diet at a concentration of 0.1%. DEHP's ability to block development of GGT+ foci correlated with its ability to increase liver weight and to induce carnitine acetyltransferase (EC 2.3.1.7), a marker of peroxisome proliferation.

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Essential role for mevalonate synthesis in DNA replication

Cited by 262 publications

References 26 publications

Mevalonate Promotes the Growth of Tumors Derived from Human Cancer Cells in Vivo and Stimulates Proliferation in Vitro with Enhanced Cyclin-dependent Kinase-2 Activity

Mevalonate Promotes the Growth of Tumors Derived from Human Cancer Cells in Vivo and Stimulates Proliferation in Vitro with Enhanced Cyclin-dependent Kinase-2 Activity

Geranylgeraniol potentiates lovastatin inhibition of oncogenic H-Ras processing and signaling while preventing cytotoxicity

Concentration-dependent inhibition of development of GGT positive foci in rat liver by the environmental contaminant di(2-ethylhexyl) phthalate.

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