Molecular crosstalk between apoptosis and autophagy induced by a novel 2-methoxyestradiol analogue in cervical adenocarcinoma cells

dc.contributor.authorTheron, Anne Elisabeth
dc.contributor.authorNolte, Elsie M.
dc.contributor.authorLafanechere, Laurence
dc.contributor.authorJoubert, Annie M.
dc.contributor.emailjoji.theron@up.ac.zaen_US
dc.date.accessioned2014-01-27T08:31:54Z
dc.date.available2014-01-27T08:31:54Z
dc.date.issued2013-08-27
dc.description.abstractBACKGROUND: 2-Methoxyestradiol has been shown to induce both autophagy and apoptosis in various carcinogenic cell lines. Although a promising anti-cancer agent, it has poor bioavailability and rapid in vivo metabolism which decreases its efficiency. In order to improve 2-methoxyestradiol’s anti-proliferative properties, a novel 2- methoxyestradiol analogue, 2-ethyl-3-O-sulphamoyl-estra-1,3,5 (10)16-tetraene (ESE-16), was previously in silicodesigned in our laboratory. This study investigated ESE-16 for its anti-proliferative potential on a cervical adenocarcinoma cell (HeLa) cell line. Additionally, the possible intracellular crosstalk mechanisms between the two types of cell death were investigated. METHODS AND RESULTS: HeLa cells exposed to 0.5 μM ESE-16 for 24 hours showed morphological evidence of both apoptotic and autophagic death pathways as assessed by polarization-optical transmitted light differential interference contrast microscopy, fluorescent microscopy and transmission electron microscopy. Flow cytometric cyclin B1 quantification revealed induction of programmed cell death after halting cell cycle progression in metaphase. Confocal microscopy demonstrated that ESE-16 caused microtubule fragmentation. Flow cytometric analysis of cell cycle progression and phosphatidylserine flip determination confirmed induction of apoptosis. Moreover, an increase in aggresome formation and microtubule-associated protein light chain, LC3, was demonstrated indicative of autophagy. Both caspase 8 and 3 were upregulated in a spectrophotometric analysis, indicating the involvement of the extrinsic pathway of apoptotic induction. CONCLUSIONS: We conclude that the novel in silico-designed compound, ESE-16, exerts its anti-proliferative effect on the tumorigenic human epithelial cervical (HeLa) cells by sequentially targeting microtubule integrity, resulting in a metaphase block, causing induction of both autophagic and apoptotic cell death via a crosstalk mechanism that involves the extrinsic pathway. Future investigations will expand on signal transduction pathways involved in both apoptosis and autophagy for assessment of ESE-16 effects on microtubule dynamic instability parameters.en_US
dc.description.librarianam2014en_US
dc.description.sponsorshipThe Cancer Association of South Africa (CANCA) (AOS201), the Medical Research Council (MRC) (AOS536), the National Research Foundation (NRF) (AOT060), The Research Committee of the University of Pretoria (RESCOM) (AOR984), South African Medical Association (SAMA) and the Research Development Programme (UP) (AOV8410).en_US
dc.description.urihttp://www.cancerci.com/content/13/1/87en_US
dc.identifier.citationTheron et al.: Molecular crosstalk between apoptosis and autophagy induced by a novel 2-methoxyestradiol analogue in cervical adenocarcinoma cells. Cancer Cell International 2013 13:87.en_US
dc.identifier.issn1475-2867 (print)
dc.identifier.issn1475-2867 (online)
dc.identifier.other10.1186/1475-2867-13-87
dc.identifier.urihttp://hdl.handle.net/2263/33111
dc.language.isoenen_US
dc.publisherBioMed Centralen_US
dc.rights© 2013 Theron et al.; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution Licenseen_US
dc.subject2-methoxyestradiolen_US
dc.subjectESE-16en_US
dc.subjectAnalogueen_US
dc.subjectApoptosisen_US
dc.subjectAutophagyen_US
dc.subjectCaspaseen_US
dc.subjectCrosstalken_US
dc.subjectMitotic blocken_US
dc.subjectMicrotubulesen_US
dc.subject2-ethyl-3-O-sulphamoyl-estra-1,3,5(10)16-tetraeneen_US
dc.titleMolecular crosstalk between apoptosis and autophagy induced by a novel 2-methoxyestradiol analogue in cervical adenocarcinoma cellsen_US
dc.typeArticleen_US

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