A novel 2-methoxyestradiol analogue is responsible for vesicle disruption and lysosome aggregation in breast cancer cells

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dc.contributor.author Nkandeu, D.S. (Danielle Sandra)
dc.contributor.author Van den Bout, Jan Iman
dc.contributor.author Cronjé, Marianne J.
dc.contributor.author Van Papendorp, D.H. (Dirk Hermanus), 1949-
dc.contributor.author Joubert, Anna Margaretha
dc.date.accessioned 2018-05-14T07:56:42Z
dc.date.issued 2018
dc.description.abstract BACKGROUND : 2-Methoxyestradiol (2ME2) is an endogenous metabolite of 17-β-estradiol with anti-proliferative and anti-angiogenic properties. Due to 2ME2’s rapid metabolism and low oral bioavailability in in vivo settings, 2ME2 analogues have been designed to alleviate these issues. One of these compounds is 2-ethyl-3-O-sulphamoyl-estra-1,3,5(10)16-tetraene (ESE-16). A previous work alluded to the ability of ESE-16 to induce autophagic cell death. Therefore, we investigated the mode of action of ESE-16 by studying its effects on autophagy, vesicle formation, and lysosomal organisation. SUMMARY : Vesicle formation and autophagy induction were analysed by transmission electron microscopy (TEM), monodansylcadaverine (MDC) staining and Lysotracker staining, while autophagosome turnover was analysed using microtubule-associated protein 1A/1B-light chain 3 (LC3 lipidation) analysis. MDC staining of acidic vesicles revealed an increase both in the number and size of vesicles after ESE-16 exposure. This was confirmed by TEM. Lysotracker staining indicated an increase in the size of lysosomes, as well as changes in their distribution within the cell. However, autophagy was not induced, since LC3 lipidation did not increase after exposure to ESE-16. KEY MESSAGES : This study showed that ESE-16 exposure leads to the aggregation of acidic vesicles, identified as lysosomes, not accompanied by an induction of autophagy. Therefore, ESE-16 disrupts normal endocytic vesicle maturation likely through the inhibition of the microtubule function. en_ZA
dc.description.department Physiology en_ZA
dc.description.embargo 2019-04-19
dc.description.librarian hj2018 en_ZA
dc.description.sponsorship Grants awarded to Prof AM Joubert from the Medical Research Council of South Africa (AOS536, AOW110, AK076; AL343), the Cancer Association of South Africa (AOW228, A0V741, AK246), RESCOM, School of Medicine (Faculty of Health Sciences, University of Pretoria), the National Research Foundation of South Africa (N00375, AL239) and the Struwig-Germeshuysen Cancer Research Trust of South Africa (AN074). en_ZA
dc.description.uri https://www.karger.com/PHA en_ZA
dc.identifier.citation Nkandeu, S.D., Van den Bout, I., Cronjé, M.J. et al. 2018, 'A novel 2-methoxyestradiol analogue is responsible for vesicle disruption and lysosome aggregation in breast cancer cells', Pharmacology, vol. 102, no. 1-2, pp. 9-16. en_ZA
dc.identifier.issn 0031-7012 (print)
dc.identifier.issn 1423-0313 (online)
dc.identifier.other 10.1159/000487443
dc.identifier.uri http://hdl.handle.net/2263/64931
dc.language.iso en en_ZA
dc.publisher Karger Publishers en_ZA
dc.rights © 2018 S. Karger AG, Basel en_ZA
dc.subject Lysosomes en_ZA
dc.subject Autophagy en_ZA
dc.subject Cancer en_ZA
dc.subject Microtubule en_ZA
dc.subject Cell signaling en_ZA
dc.subject 2-Methoxyestradiol (2ME2) en_ZA
dc.subject 2-ethyl-3-O-sulphamoyl-estra-1,3,5(10)16-tetraene (ESE-16) en_ZA
dc.subject Transmission electron microscopy (TEM) en_ZA
dc.subject monodansylcadaverine (MDC) en_ZA
dc.subject Lysotracker staining en_ZA
dc.title A novel 2-methoxyestradiol analogue is responsible for vesicle disruption and lysosome aggregation in breast cancer cells en_ZA
dc.type Postprint Article en_ZA


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