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; Lisanti, MP

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.

Citation

Fiorillo, M., Peiris-Pagès, M., Sanchez-Alvarez, R., Bartella, L., Di Donna, L., Dolce, V., …Lisanti, M. (2018). Bergamot natural products eradicate cancer stem cells (CSCs) by targeting mevalonate, Rho-GDI-signalling and mitochondrial metabolism. BBA - Bioenergetics, 1859(9), 984-996. https://doi.org/10.1016/j.bbabio.2018.03.018

• Journal Article Type: Article
• Acceptance Date: Mar 23, 2018
• Online Publication Date: Apr 4, 2018
• Publication Date: Sep 1, 2018
• Deposit Date: May 18, 2018
• Publicly Available Date: Apr 4, 2019
• Journal: Biochimica et Biophysica Acta (BBA) - Bioenergetics
• Print ISSN: 0005-2728
• Publisher: Elsevier
• Volume: 1859
• Issue: 9
• Pages: 984-996
• DOI: https://doi.org/10.1016/j.bbabio.2018.03.018
• Publisher URL: https://doi.org/10.1016/j.bbabio.2018.03.018
• Related Public URLs: https://www.journals.elsevier.com/bba-bioenergetics