Anticancer auranofin engages 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR) as a target

Auranofin (AuRF) has been reported to display anticancer activity and has entered several clinical trials; however, its mechanism of action remains largely unknown. In this work, the anticancer mechanism of auranofin was investigated using a proteomics strategy entailing subcellular fractionation pr...

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Bibliographic Details
Published in:Metallomics 2019-11, Vol.11 (11), p.1925-1936
Main Authors: Tian, Songhai, Siu, Fung-Ming, Lok, Chun-Nam, Fung, Yi Man Eva, Che, Chi-Ming
Format: Article
Language:English
Subjects:
Anticancer properties
Antitumor activity
Bioinformatics
Cancer
Cell death
Clinical trials
Coenzyme A
E2F protein
Fractionation
Hydroxymethylglutaryl-CoA reductase
Mevalonate pathway
Mevalonic acid
p53 Protein
Proteomics
Reductases
Spectrometry
Statins
Transcription
Tumor suppressor genes
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Summary:Auranofin (AuRF) has been reported to display anticancer activity and has entered several clinical trials; however, its mechanism of action remains largely unknown. In this work, the anticancer mechanism of auranofin was investigated using a proteomics strategy entailing subcellular fractionation prior to mass spectrometric analysis. Bioinformatics analysis of the nuclear sub-proteomes revealed that tumor suppressor p14 ARF is a key regulator of transcription. Through independent analysis, we validated that up-regulation of p14 ARF is associated with E2F-dependent transcription and increased p53 expression. Our analyses further reveal that 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR), which is the rate-determining enzyme of the mevalonate pathway, is a novel target of auranofin with half maximal inhibitory concentration at micromolar levels. The auranofin-induced cancer cell death could be partially reverted by the addition of downstream products of the mevalonate pathway (mevalonolactone or geranyleranyl pyrophosphate (GGPP)), implying that auranofin may target the mevalonate pathway to exert its anticancer effect. Subcellular fractionation method was used with HPLC-MS/MS technique for proteomics analysis to study the anticancer mechanism of action of auranofin. HMGCR is identified as a novel target of auranofin.
ISSN:1756-5901
1756-591X
DOI:10.1039/c9mt00185a