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Review
. 2010 Jan 28;287(2):123-35.
doi: 10.1016/j.canlet.2009.05.015. Epub 2009 Jun 10.

Molecular mechanisms involved in farnesol-induced apoptosis

Joung Hyuck Joo  1 , Anton M Jetten
Affiliations
Review

Molecular mechanisms involved in farnesol-induced apoptosis

Joung Hyuck Joo et al. Cancer Lett. .

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 alpha (CCTalpha), 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-kappaB signaling pathway and a number of NF-kappaB target genes. Optimal activation of NF-kappaB 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.

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Conflict of interest statement

Conflicts of interest statement

None declared.

Figures

Fig. 1
Fig. 1
(A) Molecular structure of farnesol and farnesol-related isoprenoids, geraniol, geranylgeraniol, and perillyl alcohol. (B) Farnesol is found in many fruits and herbs and a catabolite of the mevalonate pathway. The mevalonate pathway starts with the formation of HMG-CoA that subsequently is converted into mevalonate by HMG-CoA reductase, the rate-limiting enzyme in this pathway. Mevalonate leads to the synthesis of farnesyl-PP, which is at the branch-point of several pathways. In addition to serving as precursor of cholesterol biosynthesis, it can be converted to geranylgeranyl-PP. Both farnesyl-PP and geranylgeranyl-PP are involved in the prenylation of a variety of proteins and can be metabolized to their alcohol derivatives. HMG-CoA, 3-hydroxy-3-methylglutaryl-CoA; farnesyl-PP, farnesyl pyrophosphate; geranyl-PP, geranyl pyrophosphate; GGPP, geranylgeranyl-pyrophosphate
Fig. 1
Fig. 1
(A) Molecular structure of farnesol and farnesol-related isoprenoids, geraniol, geranylgeraniol, and perillyl alcohol. (B) Farnesol is found in many fruits and herbs and a catabolite of the mevalonate pathway. The mevalonate pathway starts with the formation of HMG-CoA that subsequently is converted into mevalonate by HMG-CoA reductase, the rate-limiting enzyme in this pathway. Mevalonate leads to the synthesis of farnesyl-PP, which is at the branch-point of several pathways. In addition to serving as precursor of cholesterol biosynthesis, it can be converted to geranylgeranyl-PP. Both farnesyl-PP and geranylgeranyl-PP are involved in the prenylation of a variety of proteins and can be metabolized to their alcohol derivatives. HMG-CoA, 3-hydroxy-3-methylglutaryl-CoA; farnesyl-PP, farnesyl pyrophosphate; geranyl-PP, geranyl pyrophosphate; GGPP, geranylgeranyl-pyrophosphate
Fig. 2
Fig. 2
Effects of exogenous farnesol on CCTα. CCTα is the rate-limiting enzyme in the CDP-choline pathway leading to the biosynthesis of phosphatidylcholine, the major membrane lipid and precursor of lipid second messengers, including phosphatidic acid (PA) and diacylglycerol (DAG). Farnesol causes translocation of CCTα to the nuclear envelope resulting in nucleoplasmic reticulum proliferation and a transient increase in CCTα activity. CCTα is subsequently exported from the nucleus. Activation of caspases during farnesol-induced apoptosis results in CCTα cleavage; however, the export of CCTα occurs independently of caspases and may be due to loss of integrity of the nuclear envelope during apoptosis. CPT, CDP-choline:1,2-diacylglycerol cholinephosphotransferase; PLD, phospholipase D; PAP, phosphatidic acid phosphatase.
Fig. 3
Fig. 3
Farnesol induces ER stress and activation of the unfolded protein response. Activation of the MEK-ERK signaling pathway by farnesol is an early event that is critical in triggering the UPR. The UPR is initiated by the activation of several ER stress-sensor proteins, including PERK, IRE1, and ATF6. Dissociation of the ER chaperone BiP/GRP78 from UPR sensor protein complexes plays a critical role in their activation. Release of BiP leads to activation and nuclear translocation of ATF6. Activation of PERK results in the phosphorylation of eIF2α and subsequently to an attenuation of the rate of general mRNA translation and protein synthesis. However, it selectively enhances the translation of some mRNAs, including the transcription factor ATF4. Active IRE1 induces alternative splicing of XBP1 mRNA resulting in the synthesis of a potent transcriptional activator. ATF4, ATF6, and XBP1 enhance the transcription of several chaperones. Activation of these pathways lead to inhibition of newly synthesized protein, increased degradation of misfolded proteins, and amplification of the protein folding capacity with the intend to restore normal ER function and promote cell survival. If ER homeostasis cannot be restored, cells start to undergo apoptosis. The IRE1-TRAF2-ASK1-JNK cascade is an important pro-apoptotic signaling pathway in ER stress. GRPs, glucose response proteins; SRPs, stress response proteins; PARP, poly(ADP-ribose) polymerase
Fig. 4
Fig. 4
Activation of the NF-κB signaling pathway by farnesol is related to ER stress. Upon activation of the UPR, activated IRE1α binds TRAF2 and recruits IKK, which subsequently phosphorylates IκB thereby promoting its degradation, while activation of the PERK-eIF2α pathway leads to attenuation of the rate of mRNA translation, including a reduction in IκBα synthesis. These events act synergistally to reduce IκBα and lead to the exposure of the nuclear localization signal of NF-κB, its translocation to the nucleus, and activation of NF-κB target genes. Activation of the MEK1/2-ERK1/2-MSK1 pathway by farnesol promotes the phosphorylation of p65/relA (Ser276) thereby enhancing NF-κB transcriptional activity.
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