| Metabolic oxidative stress elicited by the copper(II) complex [Cu(isaepy)2] triggers apoptosis in SH-SY5Y cells through the induction of AMP-activated protein kinase/p38MAPK/p53 signalling axis Evidence for a combined use with 3-bromopyruvate in neuroblastoma treatment. | |
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MedLine Citation:
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PMID: 21548882 Owner: NLM Status: Publisher |
Abstract/OtherAbstract:
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We previously demonstrated that the complex bis[(2-oxindol-3-ylimino)-2-(2-aminoethyl)pyridine-N,N']copper(II), named [Cu(isaepy)2], induces AMPK-dependent/p53-mediated apoptosis in tumour cells by targeting mitochondria. Here, we reveal that p38MAPK is the molecular link of the phosphorylative cascade connecting AMPK to p53. Transfection of SH-SY5Y with a dominant negative mutant of AMPK results in apoptosis decrease, and a significant reduction of phospho-active p38MAPK and p53. Similarly, reverse genetics of p38MAPK yields a reduction of p53 and decreases apoptotic extent, confirming an exclusive hierarchy of activation that proceeds via AMPK/p38MAPK/p53. Fuel supplies counteract [Cu(isaepy)2]-induced apoptosis and AMPK/p38MAPK/p53 activation, with glucose being the most effective, suggesting a role for energetic dysbalance in [Cu(isaepy)2] toxicity. Co-administration of 3-bromopyruvate (3BrPA), a well-known inhibitor of glycolysis and succinate dehydrogenase, enhances apoptosis and AMPK/p38MAPK/p53 signalling pathway activation. Under these conditions, no toxic effect is observed in superoxide dismutase-overexpressing SH-SY5Y, or in primary cortical neurons (PCN), which are, conversely sensitized to the combined treatment with [Cu(isaepy)2] and 3BrPA only if grown in low glucose, or incubated with the glucose-6-phosphate dehydrogenase inhibitor, dehyroepiandrosterone. Overall, the results suggest that NADPH deriving from pentose phosphate pathway contributes to PCN resistance against [Cu(isaepy)2] toxicity and propose its employment in combination with 3BrPA as possible tool for cancer treatment. |
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Authors:
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Giuseppe Filomeni; Simone Cardaci; Ana Maria Da Costa Ferreira; Giuseppe Rotilio; Maria R Ciriolo |
Publication Detail:
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Type: JOURNAL ARTICLE Date: 2011-5-6 |
Journal Detail:
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Title: The Biochemical journal Volume: - ISSN: 1470-8728 ISO Abbreviation: - Publication Date: 2011 May |
Date Detail:
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Created Date: 2011-5-9 Completed Date: - Revised Date: - |
Medline Journal Info:
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Nlm Unique ID: 2984726R Medline TA: Biochem J Country: - |
Other Details:
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Languages: ENG Pagination: - Citation Subset: - |
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From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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