The garlic compound ajoene covalently binds vimentin, disrupts the vimentin network and exerts anti-metastatic activity in cancer cells

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dc.contributor.authorKaschula, Catherine H.en_ZA
dc.contributor.authorTuveri, Rosannaen_ZA
dc.contributor.authorNgarande, Ellenen_ZA
dc.contributor.authorDzobo, Kevinen_ZA
dc.contributor.authorBarnett, Christopheren_ZA
dc.contributor.authorKusza, Daniel A.en_ZA
dc.contributor.authorGraham, Lisa M.en_ZA
dc.contributor.authorKatz, Arieh A.en_ZA
dc.contributor.authorRafudeen, Mohamed Suhailen_ZA
dc.contributor.authorParker, M. Iqbalen_ZA
dc.contributor.authorSchafer, Georgiaen_ZA
dc.date.accessioned2019-04-11T12:20:27Z
dc.date.available2019-04-11T12:20:27Z
dc.date.issued2019
dc.descriptionCITATION: Kaschula, C. H., et al. 2019. The garlic compound ajoene covalently binds vimentin, disrupts the vimentin network and exerts anti-metastatic activity in cancer cells. BMC Cancer, 19:248, doi:10.1186/s12885-019-5388-8.
dc.descriptionThe original publication is available at https://bmccancer.biomedcentral.com
dc.description.abstractBackground: Garlic has been used for centuries for its flavour and health promoting properties that include protection against cancer. The vinyl disulfide-sulfoxide ajoene is one of the phytochemicals found in crushed cloves, hypothesised to act by S-thiolating reactive cysteines in target proteins. Methods: Using our fluorescently labelled ajoene analogue called dansyl-ajoene, ajoene’s protein targets in MDAMB- 231 breast cancer cells were tagged and separated by 2D electrophoresis. A predominant band was identified by MALDI-TOF MS/MS to be vimentin. Target validation experiments were performed using pure recombinant vimentin protein. Computational modelling of vimentin bound to ajoene was performed using Schrödinger and pKa calculations by Epik software. Cytotoxicity of ajoene in MDA-MB-231 and HeLa cells was measured by the MTT assay. The vimentin filament network was visualised in ajoene-treated and non-treated cells by immunofluorescence and vimentin protein expression was determined by immunoblot. The invasion and migration activity was measured by wound healing and transwell assays using wildtype cells and cells in which the vimentin protein had been transiently knocked down by siRNA or overexpressed. Results: The dominant protein tagged by dansyl-ajoene was identified to be the 57 kDa protein vimentin. The vimentin target was validated to reveal that ajoene and dansyl-ajoene covalently bind to recombinant vimentin via a disulfide linkage at Cys-328. Computational modelling showed Cys-328 to be exposed at the termini of the vimentin tetramer. Treatment of MDA-MB-231 or HeLa cells with a non-cytotoxic concentration of ajoene caused the vimentin filament network to condense; and to increase vimentin protein expression. Ajoene inhibited the invasion and migration of both cancer cell lines which was found to be dependent on the presence of vimentin. Vimentin overexpression caused cells to become more migratory, an effect that was completely rescued by ajoene. Conclusions: The garlic-derived phytochemical ajoene targets and covalently modifies vimentin in cancer cells by S-thiolating Cys-328. This interaction results in the disruption of the vimentin filament network and contributes to the anti-metastatic activity of ajoene in cancer cells.en_ZA
dc.description.urihttps://bmccancer.biomedcentral.com/articles/10.1186/s12885-019-5388-8
dc.description.versionPublisher's version
dc.format.extent16 pagesen_ZA
dc.identifier.citationKaschula, C. H., et al. 2019. The garlic compound ajoene covalently binds vimentin, disrupts the vimentin network and exerts anti-metastatic activity in cancer cells. BMC Cancer, 19:248, doi:10.1186/s12885-019-5388-8
dc.identifier.issn1471-2407 (online)
dc.identifier.otherdoi:10.1186/s12885-019-5388-8
dc.identifier.urihttp://hdl.handle.net/10019.1/105559
dc.language.isoen_ZAen_ZA
dc.publisherBMC (part of Springer Nature)en_ZA
dc.rights.holderAuthor retains copyrighten_ZA
dc.subjectPolysulfidesen_ZA
dc.subjectAllium sativumen_ZA
dc.subjectVimentinen_ZA
dc.titleThe garlic compound ajoene covalently binds vimentin, disrupts the vimentin network and exerts anti-metastatic activity in cancer cellsen_ZA
dc.typeArticleen_ZA
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