Cancer Letters

Cancer Letters

Volume 287, Issue 2, 28 January 2010, Pages 123-135
Cancer Letters

Mini-review
Molecular mechanisms involved in farnesol-induced apoptosis

https://doi.org/10.1016/j.canlet.2009.05.015Get rights and content

Abstract

The isoprenoid alcohol farnesol is an effective inducer of cell cycle arrest and apoptosis in a variety of carcinoma cell types. In addition, farnesol has been reported to inhibit tumorigenesis in several animal models suggesting that it functions as a chemopreventative and anti-tumor agent in vivo. A number of different biochemical and cellular processes have been implicated in the growth-inhibitory and apoptosis-inducing effects of farnesol. These include regulation of 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) reductase and CTP:phosphocholine cytidylyltransferase α (CCTα), rate-limiting enzymes in the mevalonate pathway and phosphatidylcholine biosynthesis, respectively, and the generation of reactive oxygen species. In some cell types the action of farnesol is mediated through nuclear receptors, including activation of farnesoid X receptor (FXR) and peroxisome proliferator-activated receptors (PPARs). Recent studies have revealed that induction of endoplasmic reticulum (ER) stress and the subsequent activation of the unfolded protein response (UPR) play a critical role in the induction of apoptosis by farnesol in lung carcinoma cells. This induction was found to be dependent on the activation of the MEK1/2-ERK1/2 pathway. In addition, farnesol induces activation of the NF-κB signaling pathway and a number of NF-κB target genes. Optimal activation of NF-κB was reported to depend on the phosphorylation of p65/RelA by the MEK1/2-MSK1 signaling pathway. In a number of cells farnesol-induced apoptosis was found to be linked to activation of the apoptosome. This review provides an overview of the biochemical and cellular processes regulated by farnesol in relationship to its growth-inhibitory, apoptosis-promoting, and anti-tumor effects.

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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