Pleiotropic effects of a schweinfurthin on isoprenoid homeostasis

Sarah A. Holstein, Craig H. Kuder, Huaxiang Tong, Raymond Hohl

Research output: Contribution to journalArticle

12 Citations (Scopus)

Abstract

The schweinfurthins, a family of natural products derived from the isoprenoid biosynthetic pathway (IBP), have marked growth inhibitory activity. However, the biochemical basis for the schweinfurthins cellular effects has remained ill-defined. Here, the effects of the synthetic schweinfurthin, 3-deoxyschweinfurthin (3dSB) on multiple aspects of isoprenoid homeostasis are explored. Cytotoxicity assays demonstrate a synergistic interaction between 3dSB and the HMG-CoA reductase inhibitor lovastatin but not with other IBP inhibitors in a variety of human cancer cell lines. The cytotoxic effects of 3dSB were enhanced in cells incubated in lipid-depleted serum. 3dSB was found to enhance the lovastatin-induced decrease in protein prenylation. In addition, 3dSB decreases intracellular farnesyl pyrophosphate and geranylgeranyl pyrophosphate levels in both established cell lines and primary cells. To determine whether 3dSB alters the regulation of expression of genes involved in isoprenoid homeostasis, real-time PCR studies were performed in human cell lines cultured in either lipid-replete or -deplete conditions. These studies demonstrate that 3dSB abrogates lovastatin-induced upregulation of sterol regulatory element-containing genes and lovastatin-induced downregulation of ABCA1. In aggregate, these studies are the first to demonstrate that a schweinfurthin exerts pleiotropic effects on isoprenoid homeostasis.

Original languageEnglish (US)
Pages (from-to)907-921
Number of pages15
JournalLipids
Volume46
Issue number10
DOIs
StatePublished - Oct 1 2011

Fingerprint

Terpenes
Lovastatin
Homeostasis
Biosynthetic Pathways
Cells
Cell Line
Genes
Protein Prenylation
Lipids
Hydroxymethylglutaryl-CoA Reductase Inhibitors
Time and motion study
Gene Expression Regulation
Sterols
Cytotoxicity
Biological Products
Real-Time Polymerase Chain Reaction
Assays
Up-Regulation
Down-Regulation
Growth

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Cell Biology
  • Organic Chemistry

Cite this

Holstein, Sarah A. ; Kuder, Craig H. ; Tong, Huaxiang ; Hohl, Raymond. / Pleiotropic effects of a schweinfurthin on isoprenoid homeostasis. In: Lipids. 2011 ; Vol. 46, No. 10. pp. 907-921.
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Pleiotropic effects of a schweinfurthin on isoprenoid homeostasis. / Holstein, Sarah A.; Kuder, Craig H.; Tong, Huaxiang; Hohl, Raymond.

In: Lipids, Vol. 46, No. 10, 01.10.2011, p. 907-921.

Research output: Contribution to journalArticle

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