Mevalonate pathway intermediates downregulate zoledronic acid-induced isopentenyl pyrophosphate and ATP analog formation in human breast cancer cells
| Autor: | Jukka Mönkkönen, Hannu Mönkkönen, Seppo Auriola, Johanna Räikkönen |
|---|---|
| Rok vydání: | 2010 |
| Předmět: |
Farnesyl pyrophosphate
Isopentenyl pyrophosphate Down-Regulation Mevalonic Acid Breast Neoplasms Zoledronic Acid Biochemistry chemistry.chemical_compound Adenosine Triphosphate Hemiterpenes Organophosphorus Compounds Geranylgeraniol Cell Line Tumor medicine Anticarcinogenic Agents Humans Pharmacology Diphosphonates ATP synthase biology Imidazoles Farnesol Gene Expression Regulation Neoplastic chemistry Mechanism of action biology.protein Protein prenylation Female Mevalonate pathway Drug Screening Assays Antitumor medicine.symptom |
| Zdroj: | Biochemical Pharmacology. 79:777-783 |
| ISSN: | 0006-2952 |
| Popis: | Increasing evidence is accumulating that zoledronic acid (ZOL), a nitrogen-containing bisphosphonate (N-BP), is able to affect tumor cells by inhibiting the enzyme farnesyl pyrophosphate synthase (FPPS) in the mevalonate pathway (MVP). The consequent accumulation of unprenylated proteins is believed to largely account for the cytotoxic effects of ZOL. FPPS inhibition leads also to the accumulation of isopentenyl pyrophosphate (IPP) and the apoptotic ATP analog, ApppI, but the role of this mechanism in the cytotoxic action of bisphosphonates is less clear. Since treatment with MVP intermediates has been shown to overcome N-BP-induced apoptosis via rescuing protein prenylation, our aim here was to determine their mechanism of action on ZOL-induced IPP/ApppI accumulation. Interestingly, the results revealed that ZOL-induced IPP/ApppI accumulation in MCF-7 cells were decreased by farnesol, and almost completely blocked by geranylgeraniol and geranylpyrophosphate. The functionality of the regulatory enzymes of IPP and ApppI, IPP isomerase and aminoacyl-tRNA-synthase, respectively, or protein levels of FPPS were not affected by the treatments. However, the protein levels of 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGR) and unprenylated Rap1A were observed to be strongly downregulated by geranylgeraniol and geranylpyrophosphate. This study represents a novel insight into the mechanism of action of MVP intermediates on the regulation of MVP after FPPS inhibition. The data implies that in addition to the previously reported effects on rescuing protein prenylation, MVP intermediates can preserve cell activity by inhibiting the accumulation of IPP/ApppI via HMGR downregulation. This supports the hypothesis that IPP/ApppI formation is a significant mechanism in the anticancer action of ZOL. |
| Databáze: | OpenAIRE |
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