Mini-reviewMolecular mechanisms involved in farnesol-induced apoptosis
Introduction
Isoprenoids are essential in the regulation of cell proliferation, apoptosis, differentiation, and lipid biosynthesis [1], [2], [3], [4], [5], [6], [7], [8], [9]. The isoprenoid pathway leads to the synthesis of farnesyl pyrophosphate (farnesyl-PP) and to geranylgeranyl pyrophosphate (geranylgeranyl-PP) which are involved in the prenylation of many proteins, and subsequently the biosynthesis of cholesterol, sterols, and other cholesterol derivatives [6], [8], [9], [10]. The non-sterol isoprenoid farnesol is produced by dephosphorylation of farnesyl-PP, a metabolite of the cholesterol biosynthetic pathway. In addition to being produced endogenously, farnesol and the related isoprenoids (Fig. 1A), perillyl alcohol and geraniol, are natural compounds found in many fruits and aromatic plants, including citrus (perillyl alcohol, geraniol), sage, spearmint, nutmeg (perillyl alcohol), basil (geraniol), lemon grass (farnesol and geraniol), and chamomile (farnesol) [11], [12], [13]. This article reviews the current status of our knowledge of the effects of farnesol on mammalian cell proliferation, differentiation, apoptosis, and tumor suppression.
Section snippets
In vitro cell systems
A number of studies have demonstrated that farnesol and related isoprenoids, including geraniol and perillyl alcohol, inhibit cell proliferation and induce apoptosis in a broad range of malignant cell types. Tumor cells were generally found to be considerably more sensitive to farnesol-induced growth inhibition than normal cells [2], [14], [15]. For example, in contrast to leukemic cells, human primary T lymphocytes or monocytes are rather resistant to farnesol-induced apoptosis. The mechanism
Effect of farnesol on HMG-CoA reductase
Initial studies indicated that the inhibition of cell proliferation and induction of apoptosis by farnesol might relate to its inhibitory effect on 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) reductase, an enzyme that converts HMG-CoA into mevalonate, the rate-limiting step in the isoprenoid biosynthetic pathway (Fig. 1B)[8], [9], [66]. Mevalonate leads to the synthesis of farnesyl-PP, which serves as a precursor of cholesterol biosynthesis, and can be converted to geranylgeranyl pyrophosphate
Farnesol and the farnesoid X receptor (FXR)
Farnesol has been reported to activate the nuclear receptor, farnesoid X receptor (FXR, NR1H4) [133], [134]. FXR is highly expressed in the liver, gut, kidney and adrenal cortex and regulates a variety of genes with roles in bile acid homeostasis, lipid and glucose metabolism [135], [136]. FXR is activated by several conjugated and unconjugated bile acids, including lithocholic acid, chenodeoxycholic acid, and deoxycholic acid which bind FXR with high affinity [137], [138], [139]. A large
Summary
The anti-tumor and chemopreventative effects of farnesol appear to involve several different mechanisms that can act at either the initiation or progression stage of tumorigenesis. Reduction of carcinogen-induced DNA strand breaks and of the formation of DNA adducts by farnesol suggests that its anti-tumorigenic effects may be a consequence of an inhibition at the initiation stage of tumorigenesis. Similarly, the protective effect of farnesol against cigarette smoke-induced lung injury and
Conflicts of interest
None declared.
Acknowledgements
The authors would like to thank Drs. Carl Bortner and Gary Zeruth (NIEHS) for their comments on the manuscript. This research was supported by the Intramural Research Program of the NIEHS, NIH (Z01-ES-101586).
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