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

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

Author Queiroz, Karla C. S. Google Scholar
Milani, Renato Google Scholar
Ruela-de-Sousa, Roberta R. Google Scholar
Fuhler, Gwenny M. Google Scholar
Justo, Giselle Zenker Autor UNIFESP Google Scholar
Zambuzzi, Willian F. Google Scholar
Duran, Nelson Google Scholar
Diks, Sander H. Google Scholar
Spek, C. Arnold Google Scholar
Ferreira, Carmen V. Google Scholar
Peppelenbosch, Maikel P. Google Scholar
Institution Erasmus MC Univ Med Ctr
Univ Amsterdam
Universidade Estadual de Campinas (UNICAMP)
Universidade Federal de São Paulo (UNIFESP)
Univ Grande Rio UNIGRANRIO
Natl Inst Metrol Qual & Technol Inmetro
Univ Groningen
Abstract It 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.
Language English
Sponsor TopInstitute pharma (The Netherlands)
Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)
Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)
Dutch Cancer Society
Grant number Dutch Cancer Society: EMCR 2010-4737
Date 2012-10-11
Published in Plos One. San Francisco: Public Library Science, v. 7, n. 10, 8 p., 2012.
ISSN 1932-6203 (Sherpa/Romeo, impact factor)
Publisher Public Library Science
Extent 8
Access rights Open access Open Access
Type Article
Web of Science ID WOS:000309807700009

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