Novel Salvage Pathway Utilizing Farnesol and Geranylgeraniol for Protein Isoprenylation

Crick, Dean C.; Andres, Douglas A.; Waechter, Charles J.

doi:10.1006/bbrc.1997.7145

Cited by 139 publications

(130 citation statements)

References 44 publications

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“…In most studies designed to investigate this potential mechanism in osteoclasts and macrophages, the ability of FOH and GGOH to prevent effects of N-BPs have been utilised. These analogues of FPP and GGPP have been reported to display greater membrane permeability and be converted to the respective pyrophosphate forms intracellularly by a salvage pathway (Crick et al, 1997). In osteoclasts, N-BP-induced apoptosis was attenuated by addition of GGOH but not FOH (Fisher et al, 1999;van Beek et al, 1999b).…”

Section: Discussionmentioning

confidence: 99%

The bisphosphonate zoledronic acid impairs membrane localisation and induces cytochrome c release in breast cancer cells

Mansi

2002

Br J Cancer

128

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Bisphosphonates are well established in the management of cancer-induced bone disease. Recent studies have indicated that these compounds have direct inhibitory effects on cultured human breast cancer cells. Nitrogen-containing bisphosphonates including zoledronic acid have been shown to induce apoptosis associated with PARP cleavage and DNA fragmentation. The aim of this study was to identify the signalling pathways involved. Forced expression of the anti-apoptotic protein bcl-2 attenuated bisphosphonate-induced loss of cell viability and induction of DNA fragmentation in MDA-MB-231 cells. Zoledronic acid-mediated apoptosis was associated with a time and dose-related release of mitochondrial cytochrome c into the cytosol in two cell lines. Rescue of cells by preincubation with a caspase-3 selective inhibitor and demonstration of procaspase-3 cleavage products by immunoblotting suggests that at least one of the caspases activated in response to zoledronic acid treatment is caspase-3. In both MDA-MB-231 and MCF-7 breast cancer cells, zoledronic acid impaired membrane localisation of Ras indicating reduced prenylation of this protein. These observations demonstrate that zoledronic acidmediated apoptosis is associated with cytochrome c release and consequent caspase activation. This process may be initiated by inhibition of the enzymes in the mevalonate pathway leading to impaired prenylation of key intracellular proteins including Ras.

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Section: Discussionmentioning

confidence: 99%

The bisphosphonate zoledronic acid impairs membrane localisation and induces cytochrome c release in breast cancer cells

Mansi

2002

Br J Cancer

128

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“…Possible explanations for this prolonged effect include: 1) geranylgeranyltransferase I may prenylate Rac-1 more efficiently than RhoA, or 2) prenylation of Rac-1 may be less substrate dependent. Even during lovastatin treatment, prenylation substrates (GGPP or FPP) would be expected to be present in small quantities due to incomplete blockade of HMG-CoA reductase, or due to salvage pathway activity (75). Alternatively, 3) the half-life of prenylated Rac-1 may be longer than prenylated RhoA.…”

Section: Discussionmentioning

confidence: 99%

Lovastatin Enhances Clearance of Apoptotic Cells (Efferocytosis) with Implications for Chronic Obstructive Pulmonary Disease

Morimoto

Janssen²,

Fessler³

et al. 2006

The Journal of Immunology

201

179

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Statins are potent, cholesterol-lowering agents with newly appreciated, broad anti-inflammatory properties, largely based upon their ability to block the prenylation of Rho GTPases, including RhoA. Because phagocytosis of apoptotic cells (efferocytosis) is a pivotal regulator of inflammation, which is inhibited by RhoA, we sought to determine whether statins enhanced efferocytosis. The effect of lovastatin on efferocytosis was investigated in primary human macrophages, in the murine lung, and in human alveolar macrophages taken from patients with chronic obstructive pulmonary disease. In this study, we show that lovastatin increased efferocytosis in vitro in an 3-hydroxyl-3-methylglutaryl coenzyme A (HMG-CoA) reductase-dependent manner. Lovastatin acted by inhibiting both geranylgeranylation and farnesylation, and not by altering expression of key uptake receptors or by increasing binding of apoptotic cells to phagocytes. Lovastatin appeared to exert its positive effect on efferocytosis by inhibiting RhoA, because it 1) decreased membrane localization of RhoA, to a greater extent than Rac-1, and 2) prevented impaired efferocytosis by lysophosphatidic acid, a potent inducer of RhoA. Finally, lovastatin increased efferocytosis in the naive murine lung and ex vivo in chronic obstructive pulmonary disease alveolar macrophages in an HMG-CoA reductase-dependent manner. These findings indicate that statins enhance efferocytosis in vitro and in vivo, and suggest that they may play an important therapeutic role in diseases where efferocytosis is impaired and inflammation is dysregulated.

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“…However, our observations argue against a major contribution of Ras inhibition to the anticancer activity of ZOL in osteosarcoma cells. GGOH which can be taken up by cells and converted to geranylgeranyl pyrophosphate as a salvage pathway after blockade of the mevalonate pathway 31 was by far more active in reversing ZOL anticancer activity as compared to FOH. Ras, however, is primarily farnesylated and only in case of farnesyl pyrophosphate deficiency K-ras can also be geranylgeranylated, a phenomenon known as alternate prenylation.…”

Section: Discussionmentioning

confidence: 99%

Anticancer effects of zoledronic acid against human osteosarcoma cells

Kubista

Trieb

Sevelda

et al. 2006

Journal Orthopaedic Research

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Based on neoadjuvant chemotherapy, the prognosis of osteosarcoma patients has improved dramatically. However, due to therapy resistance in patient subgroups, the development of new treatment strategies is still of utmost importance. The aim of our study was to test the effects of the nitrogen-containing bisphosphonate zoledronic acid (ZOL) on osteosarcoma cell lines (N ¼ 9). Exposure to ZOL at low micromolar concentrations induced a dose-and time-dependent block of DNA synthesis and cell cycle progression followed by microfilament breakdown and apoptosis induction. The ZOL-induced cell cycle accumulation in S phase was accompanied by significant changes in the expression of cyclins and cyclin-dependent kinase inhibitors with a prominent loss of cyclin E and D1. ZOL not only inhibited growth but also migration of osteosarcoma cells. The mevalonate pathway intermediary geranyl-geraniol (GGOH) but not farnesol (FOH) significantly inhibited the anticancer effects of ZOL against osteosarcoma cells. Correspondingly, ZOL sensitivity correlated with the blockade of protein geranylgeranylation indicated by unprenylated Rap1. Overexpression of even high levels of P-glycoprotein, as frequently present in therapy-resistant osteosarcomas, did not impair the anticancer activity of ZOL. Summarizing, our data suggest that ZOL, which selectively accumulates in the bone, represents a promising agent to improve osteosarcoma therapy. ß

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Novel Salvage Pathway Utilizing Farnesol and Geranylgeraniol for Protein Isoprenylation

Cited by 139 publications

References 44 publications

The bisphosphonate zoledronic acid impairs membrane localisation and induces cytochrome c release in breast cancer cells

The bisphosphonate zoledronic acid impairs membrane localisation and induces cytochrome c release in breast cancer cells

Lovastatin Enhances Clearance of Apoptotic Cells (Efferocytosis) with Implications for Chronic Obstructive Pulmonary Disease

Anticancer effects of zoledronic acid against human osteosarcoma cells

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