Bergamot natural products eradicate cancer stem cells (CSCs) by targeting mevalonate, Rho-GDI-signalling and mitochondrial metabolism

Fiorillo, M, Peiris-Pagès, M, Sanchez-Alvarez, R, Bartella, L, Di Donna, L, Dolce, V, Sindona, G, Sotgia, F, Cappello, AR and Lisanti, MP 2018, 'Bergamot natural products eradicate cancer stem cells (CSCs) by targeting mevalonate, Rho-GDI-signalling and mitochondrial metabolism' , Biochimica et Biophysica Acta (BBA) - Bioenergetics, 1859 (9) , pp. 984-996.

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Abstract

Here, we show that a 2:1 mixture of Brutieridin and Melitidin, termed “BMF”, has a statin-like properties, which blocks the action of the rate-limiting enzyme for mevalonate biosynthesis, namely HMGR (3-hydroxy-3-methylglutaryl- CoA-reductase). Moreover, our results indicate that BMF functionally inhibits several key characteristics of CSCs. More specifically, BMF effectively i) reduced ALDH activity, ii) blocked mammosphere formation and iii) inhibited the activation of CSC-associated signalling pathways (STAT1/3, Notch and Wnt/ beta-catenin) targeting Rho-GDI-signalling. In addition, BMF metabolically inhibited mitochondrial respiration (OXPHOS) and fatty acid oxidation (FAO). Importantly, BMF did not show the same toxic side-effects in normal fibroblasts that were observed with statins. Lastly, we show that high expression of the mRNA species encoding HMGR is associated with poor clinical outcome in breast cancer patients, providing a potential companion diagnostic for BMF-directed personalized therapy.

Item Type: Article
Schools: Schools > School of Environment and Life Sciences > Biomedical Research Centre
Journal or Publication Title: Biochimica et Biophysica Acta (BBA) - Bioenergetics
Publisher: Elsevier
ISSN: 0005-2728
Related URLs:
Depositing User: M Fiorillo
Date Deposited: 18 May 2018 13:41
Last Modified: 04 Apr 2019 08:00
URI: http://usir.salford.ac.uk/id/eprint/46861

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