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Issue 11, 2019
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Anticancer auranofin engages 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR) as a target

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Abstract

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 p14ARF is a key regulator of transcription. Through independent analysis, we validated that up-regulation of p14ARF 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.

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

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Publication details

The article was received on 18 Jul 2019, accepted on 03 Oct 2019 and first published on 21 Oct 2019


Article type: Paper
DOI: 10.1039/C9MT00185A
Metallomics, 2019,11, 1925-1936

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

    S. Tian, F. Siu, C. Lok, Y. M. E. Fung and C. Che, Metallomics, 2019, 11, 1925
    DOI: 10.1039/C9MT00185A

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