Violacein Induces Death of Resistant Leukaemia Cells via Kinome Reprogramming, Endoplasmic Reticulum Stress and Golgi Apparatus Collapse

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dc.contributor.authorQueiroz, Karla C. S.
dc.contributor.authorMilani, Renato
dc.contributor.authorRuela-de-Sousa, Roberta R.
dc.contributor.authorFuhler, Gwenny M.
dc.contributor.authorJusto, Giselle Zenker [UNIFESP]
dc.contributor.authorZambuzzi, Willian F.
dc.contributor.authorDuran, Nelson
dc.contributor.authorDiks, Sander H.
dc.contributor.authorSpek, C. Arnold
dc.contributor.authorFerreira, Carmen V.
dc.contributor.authorPeppelenbosch, Maikel P.
dc.contributor.institutionErasmus MC Univ Med Ctr
dc.contributor.institutionUniv Amsterdam
dc.contributor.institutionUniversidade Estadual de Campinas (UNICAMP)
dc.contributor.institutionUniversidade Federal de São Paulo (UNIFESP)
dc.contributor.institutionUniv Grande Rio UNIGRANRIO
dc.contributor.institutionNatl Inst Metrol Qual & Technol Inmetro
dc.contributor.institutionUniv Groningen
dc.date.accessioned2016-01-24T14:27:53Z
dc.date.available2016-01-24T14:27:53Z
dc.date.issued2012-10-11
dc.description.abstractIt is now generally recognised that different modes of programmed cell death (PCD) are intimately linked to the cancerous process. However, the mechanism of PCD involved in cancer chemoprevention is much less clear and may be different between types of chemopreventive agents and tumour cell types involved. Therefore, from a pharmacological view, it is crucial during the earlier steps of drug development to define the cellular specificity of the candidate as well as its capacity to bypass dysfunctional tumoral signalling pathways providing insensitivity to death stimuli. Studying the cytotoxic effects of violacein, an antibiotic dihydro-indolone synthesised by an Amazon river Chromobacterium, we observed that death induced in CD34(+)/c-Kit(+)/P-glycoprotein(+)/MRP1(+) TF1 leukaemia progenitor cells is not mediated by apoptosis and/or autophagy, since biomarkers of both types of cell death were not significantly affected by this compound. To clarify the working mechanism of violacein, we performed kinome profiling using peptide arrays to yield comprehensive descriptions of cellular kinase activities. Pro-death activity of violacein is actually carried out by inhibition of calpain and DAPK1 and activation of PKA, AKT and PDK, followed by structural changes caused by endoplasmic reticulum stress and Golgi apparatus collapse, leading to cellular demise. Our results demonstrate that violacein induces kinome reprogramming, overcoming death signaling dysfunctions of intrinsically resistant human leukaemia cells.en
dc.description.affiliationErasmus MC Univ Med Ctr, Dept Gastroenterol & Hepatol, Rotterdam, Netherlands
dc.description.affiliationUniv Amsterdam, Acad Med Ctr, Ctr Expt & Mol Med, NL-1105 AZ Amsterdam, Netherlands
dc.description.affiliationUniv Estadual Campinas, Brazil UNICAMP, Dept Biochem, Inst Biol, São Paulo, Brazil
dc.description.affiliationFed Univ São Paulo UNIFESP, Dept Biochem, São Paulo, Brazil
dc.description.affiliationFed Univ São Paulo UNIFESP, Dept Cell Biol, São Paulo, Brazil
dc.description.affiliationUniv Grande Rio UNIGRANRIO, Heath Sci Sch, Multidisciplinary Lab Dent Res, Rio de Janeiro, Brazil
dc.description.affiliationNatl Inst Metrol Qual & Technol Inmetro, Biotechnol Lab, Bioengn Sect, Rio de Janeiro, Brazil
dc.description.affiliationUniv Campinas UNICAMP, Inst Chem, Biol Chem Lab, Rio de Janeiro, Brazil
dc.description.affiliationUniv Groningen, Univ Med Ctr Groningen, Dept Pediat Oncol, Beatrix Childrens Hosp, Groningen, Netherlands
dc.description.affiliationUnifespFed Univ São Paulo UNIFESP, Dept Biochem, São Paulo, Brazil
dc.description.affiliationUnifespFed Univ São Paulo UNIFESP, Dept Cell Biol, São Paulo, Brazil
dc.description.sourceWeb of Science
dc.description.sponsorshipTopInstitute pharma (The Netherlands)
dc.description.sponsorshipFundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)
dc.description.sponsorshipConselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)
dc.description.sponsorshipDutch Cancer Society
dc.description.sponsorshipIDDutch Cancer Society: EMCR 2010-4737
dc.format.extent8
dc.identifierhttp://dx.doi.org/10.1371/journal.pone.0045362
dc.identifier.citationPlos One. San Francisco: Public Library Science, v. 7, n. 10, 8 p., 2012.
dc.identifier.doi10.1371/journal.pone.0045362
dc.identifier.fileWOS000309807700009.pdf
dc.identifier.issn1932-6203
dc.identifier.urihttp://repositorio.unifesp.br/handle/11600/35410
dc.identifier.wosWOS:000309807700009
dc.language.isoeng
dc.publisherPublic Library Science
dc.relation.ispartofPlos One
dc.rightsAcesso aberto
dc.titleViolacein Induces Death of Resistant Leukaemia Cells via Kinome Reprogramming, Endoplasmic Reticulum Stress and Golgi Apparatus Collapseen
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