Suppression of the proliferation of Ras-transformed cells by fluoromevalonate, an inhibitor of mevalonate metabolism

J. A. Cuthbert, P. E. Lipsky

Research output: Contribution to journalArticle

27 Citations (Scopus)

Abstract

Mevalonate is the precursor of a number of different products potentially required for the growth of cells, including the prenylated oncoprotein Ras. To determine whether inhibition of mevalonate metabolism would selectively block proliferation of Ras-transformed cells, 6-fluoro-mevalonate (Fmev), an inhibitor of diphosphomevalonate decarboxylase, was used to block the synthesis of prenyl-derived lipids and prenylated proteins in interleukin-3 (IL-3)-dependent FDC-P1 cells (control FDC-P1 cells) and FDC-P1 cells transformed with oncogenic Ras (RasDC cells) that proliferated in the absence of IL-3. Fmev completely inhibited synthesis of prenyl-derived lipids and prenylated proteins and blocked proliferation of FDC-P1 and RasDC cells. Restoration of the proliferation of Fmev-blocked FDC-P1 cells required both an exogenous source of cholesterol and prevention of the accumulation of mevalonate and the mevalonate phosphates with lovastatin. In contrast, ongoing IL-3-independent proliferation of Fmev-blocked RasDC cells was not completely restored by providing exogenous cholesterol and preventing the accumulation of inhibitory mevalonate product(s). However, these cells proliferated when cultures were supplemented with IL-3 together with exogenous cholesterol and lovastatin, implying that Fmev had prevented Ras- dependent, IL-3-independent growth. Fmev markedly diminished total cellular Ras in RasDC cells. In contrast, lovastatin depleted membrane-associated Ras and increased cytosolic Ras but did not diminish total cellular Ras. These data indicate that Fmev depletes total cellular Ras and specifically inhibits the autonomous growth of Ras-transformed cells.

Original languageEnglish (US)
Pages (from-to)1732-1740
Number of pages9
JournalCancer Research
Volume55
Issue number8
StatePublished - 1995

Fingerprint

Mevalonic Acid
Interleukin-3
Lovastatin
Cholesterol
pyrophosphomevalonate decarboxylase
Growth
Lipids
Oncogene Proteins
Proteins

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Suppression of the proliferation of Ras-transformed cells by fluoromevalonate, an inhibitor of mevalonate metabolism. / Cuthbert, J. A.; Lipsky, P. E.

In: Cancer Research, Vol. 55, No. 8, 1995, p. 1732-1740.

Research output: Contribution to journalArticle

@article{de362172195e4a3ebf8f3c2f228160b7,
title = "Suppression of the proliferation of Ras-transformed cells by fluoromevalonate, an inhibitor of mevalonate metabolism",
abstract = "Mevalonate is the precursor of a number of different products potentially required for the growth of cells, including the prenylated oncoprotein Ras. To determine whether inhibition of mevalonate metabolism would selectively block proliferation of Ras-transformed cells, 6-fluoro-mevalonate (Fmev), an inhibitor of diphosphomevalonate decarboxylase, was used to block the synthesis of prenyl-derived lipids and prenylated proteins in interleukin-3 (IL-3)-dependent FDC-P1 cells (control FDC-P1 cells) and FDC-P1 cells transformed with oncogenic Ras (RasDC cells) that proliferated in the absence of IL-3. Fmev completely inhibited synthesis of prenyl-derived lipids and prenylated proteins and blocked proliferation of FDC-P1 and RasDC cells. Restoration of the proliferation of Fmev-blocked FDC-P1 cells required both an exogenous source of cholesterol and prevention of the accumulation of mevalonate and the mevalonate phosphates with lovastatin. In contrast, ongoing IL-3-independent proliferation of Fmev-blocked RasDC cells was not completely restored by providing exogenous cholesterol and preventing the accumulation of inhibitory mevalonate product(s). However, these cells proliferated when cultures were supplemented with IL-3 together with exogenous cholesterol and lovastatin, implying that Fmev had prevented Ras- dependent, IL-3-independent growth. Fmev markedly diminished total cellular Ras in RasDC cells. In contrast, lovastatin depleted membrane-associated Ras and increased cytosolic Ras but did not diminish total cellular Ras. These data indicate that Fmev depletes total cellular Ras and specifically inhibits the autonomous growth of Ras-transformed cells.",
author = "Cuthbert, {J. A.} and Lipsky, {P. E.}",
year = "1995",
language = "English (US)",
volume = "55",
pages = "1732--1740",
journal = "Journal of Cancer Research",
issn = "0099-7013",
publisher = "American Association for Cancer Research Inc.",
number = "8",

}

TY - JOUR

T1 - Suppression of the proliferation of Ras-transformed cells by fluoromevalonate, an inhibitor of mevalonate metabolism

AU - Cuthbert, J. A.

AU - Lipsky, P. E.

PY - 1995

Y1 - 1995

N2 - Mevalonate is the precursor of a number of different products potentially required for the growth of cells, including the prenylated oncoprotein Ras. To determine whether inhibition of mevalonate metabolism would selectively block proliferation of Ras-transformed cells, 6-fluoro-mevalonate (Fmev), an inhibitor of diphosphomevalonate decarboxylase, was used to block the synthesis of prenyl-derived lipids and prenylated proteins in interleukin-3 (IL-3)-dependent FDC-P1 cells (control FDC-P1 cells) and FDC-P1 cells transformed with oncogenic Ras (RasDC cells) that proliferated in the absence of IL-3. Fmev completely inhibited synthesis of prenyl-derived lipids and prenylated proteins and blocked proliferation of FDC-P1 and RasDC cells. Restoration of the proliferation of Fmev-blocked FDC-P1 cells required both an exogenous source of cholesterol and prevention of the accumulation of mevalonate and the mevalonate phosphates with lovastatin. In contrast, ongoing IL-3-independent proliferation of Fmev-blocked RasDC cells was not completely restored by providing exogenous cholesterol and preventing the accumulation of inhibitory mevalonate product(s). However, these cells proliferated when cultures were supplemented with IL-3 together with exogenous cholesterol and lovastatin, implying that Fmev had prevented Ras- dependent, IL-3-independent growth. Fmev markedly diminished total cellular Ras in RasDC cells. In contrast, lovastatin depleted membrane-associated Ras and increased cytosolic Ras but did not diminish total cellular Ras. These data indicate that Fmev depletes total cellular Ras and specifically inhibits the autonomous growth of Ras-transformed cells.

AB - Mevalonate is the precursor of a number of different products potentially required for the growth of cells, including the prenylated oncoprotein Ras. To determine whether inhibition of mevalonate metabolism would selectively block proliferation of Ras-transformed cells, 6-fluoro-mevalonate (Fmev), an inhibitor of diphosphomevalonate decarboxylase, was used to block the synthesis of prenyl-derived lipids and prenylated proteins in interleukin-3 (IL-3)-dependent FDC-P1 cells (control FDC-P1 cells) and FDC-P1 cells transformed with oncogenic Ras (RasDC cells) that proliferated in the absence of IL-3. Fmev completely inhibited synthesis of prenyl-derived lipids and prenylated proteins and blocked proliferation of FDC-P1 and RasDC cells. Restoration of the proliferation of Fmev-blocked FDC-P1 cells required both an exogenous source of cholesterol and prevention of the accumulation of mevalonate and the mevalonate phosphates with lovastatin. In contrast, ongoing IL-3-independent proliferation of Fmev-blocked RasDC cells was not completely restored by providing exogenous cholesterol and preventing the accumulation of inhibitory mevalonate product(s). However, these cells proliferated when cultures were supplemented with IL-3 together with exogenous cholesterol and lovastatin, implying that Fmev had prevented Ras- dependent, IL-3-independent growth. Fmev markedly diminished total cellular Ras in RasDC cells. In contrast, lovastatin depleted membrane-associated Ras and increased cytosolic Ras but did not diminish total cellular Ras. These data indicate that Fmev depletes total cellular Ras and specifically inhibits the autonomous growth of Ras-transformed cells.

UR - http://www.scopus.com/inward/record.url?scp=0028959503&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0028959503&partnerID=8YFLogxK

M3 - Article

C2 - 7712482

AN - SCOPUS:0028959503

VL - 55

SP - 1732

EP - 1740

JO - Journal of Cancer Research

JF - Journal of Cancer Research

SN - 0099-7013

IS - 8

ER -