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Curcumin and derivatives function through protein phosphatase 2A and presenilin orthologues in Dictyostelium discoideum.

Cocorocchio, M; Baldwin, AJ; Stewart, B; Kim, L; Harwood, AJ; Thompson, CRL; Andrews, PLR; Williams, RSB (2018) Curcumin and derivatives function through protein phosphatase 2A and presenilin orthologues in Dictyostelium discoideum. Dis Model Mech, 11 (1). dmm032375. ISSN 1754-8411 https://doi.org/10.1242/dmm.032375
SGUL Authors: Andrews, Paul Lyn Rodney

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Abstract

Natural compounds often have complex molecular structures and unknown molecular targets. These characteristics make them difficult to analyse using a classical pharmacological approach. Curcumin, the main curcuminoid of turmeric, is a complex molecule possessing wide-ranging biological activities, cellular mechanisms and roles in potential therapeutic treatment including Alzheimer's disease and cancer. Here, we investigate the physiological effects and molecular targets of curcumin in Dictyostelium discoideum We show curcumin causes acute effects on cell behaviour, reduces cell growth, and slows multicellular development. We then employ a range of structurally related compounds to show the distinct role of different structural groups cell behaviour, growth, and development, highlighting active moieties in cell function, and showing that these cellular effects are unrelated to the well-known antioxidant activity of curcumin. Molecular mechanisms underlying the effect of curcumin and one synthetic analogue (EF24) were then investigated to identify a curcumin-resistant mutant lacking the protein phosphatase 2A regulatory subunit (PsrA) and an EF24-resistant mutant lacking the presenilin 1 orthologue (PsenB). Using in-silico docking analysis, we then show that curcumin may function through direct binding to a key regulatory region of PsrA. These findings reveal novel cellular and molecular mechanisms for the function of curcumin and related compounds.

Item Type: Article
Additional Information: © 2018. Published by The Company of Biologists Ltd This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution and reproduction in any medium provided that the original work is properly attributed.
Keywords: Alzheimer's disease, Cancer, Curcumin, Dictyostelium discoideum, PP2A, Presenilin, Developmental Biology, 06 Biological Sciences, 11 Medical And Health Sciences
SGUL Research Institute / Research Centre: Academic Structure > Institute of Medical & Biomedical Education (IMBE)
Academic Structure > Institute of Medical & Biomedical Education (IMBE) > Centre for Biomedical Education (INMEBE)
Journal or Publication Title: Dis Model Mech
ISSN: 1754-8411
Language: eng
Dates:
DateEvent
29 January 2018Published
28 December 2017Published Online
28 November 2017Accepted
Publisher License: Creative Commons: Attribution 3.0
Projects:
Project IDFunderFunder ID
101582Z/13/ZWellcome Trusthttp://dx.doi.org/10.13039/100004440
PubMed ID: 29361519
Go to PubMed abstract
URI: https://openaccess.sgul.ac.uk/id/eprint/109589
Publisher's version: https://doi.org/10.1242/dmm.032375

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