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Autophagy-dependent and -independent involvement of AMP-activated protein kinase in 6-hydroxydopamine toxicity to SH-SY5Y neuroblastoma cells
dc.creator | Arsikin-Csordas, Katarina | |
dc.creator | Kravić-Stevović, Tamara | |
dc.creator | Jovanović, Maja | |
dc.creator | Ristić, Biljana | |
dc.creator | Tovilović-Kovačević, Gordana | |
dc.creator | Zogović, Nevena | |
dc.creator | Bumbaširević, Vladimir | |
dc.creator | Trajković, Vladimir | |
dc.creator | Harhaji-Trajković, Ljubica | |
dc.date.accessioned | 2023-11-27T14:25:34Z | |
dc.date.available | 2023-11-27T14:25:34Z | |
dc.date.issued | 2012 | |
dc.identifier.issn | 0925-4439 | |
dc.identifier.uri | http://radar.ibiss.bg.ac.rs/handle/123456789/6366 | |
dc.description.abstract | The role of the main intracellular energy sensor adenosine monophosphate (AMP)-activated protein kinase (AMPK) in the induction of autophagic response and cell death was investigated in SH-SY5Y human neuroblastoma cells exposed to the dopaminergic neurotoxin 6-hydroxydopamine (6-OHDA). The induction of autophagy in SH-SY5Y cells was demonstrated by acridine orange staining of intracellular acidic vesicles, the presence of autophagosome- and autophagolysosome-like vesicles confirmed by transmission electron microscopy, as well as by microtubule-associated protein 1 light-chain 3 (LC3) conversion and p62 degradation detected by immunoblotting. 6-OHDA induced phosphorylation of AMPK and its target Raptor, followed by the dephosphorylation of the major autophagy inhibitor mammalian target of rapamycin (mTOR) and its substrate p70S6 kinase (S6K). 6-OHDA treatment failed to suppress mTOR/S6K phosphorylation and to increase LC3 conversion, p62 degradation and cytoplasmatic acidification in neuroblastoma cells in which AMPK expression was downregulated by RNA interference. Transfection of SH-SY5Y cells with AMPK or LC3β shRNA, as well as treatment with pharmacological autophagy inhibitors suppressed, while mTOR inhibitor rapamycin potentiated 6-OHDA-induced oxidative stress and apoptotic cell death. 6-OHDA induced phosphorylation of p38 mitogen-activated protein (MAP) kinase in an AMPK-dependent manner, and pharmacological inhibition of p38 MAP kinase reduced neurotoxicity, but not AMPK activation and autophagy triggered by 6-OHDA. Finally, the antioxidant N-acetyl cysteine antagonized 6-OHDA-induced activation of AMPK, p38 and autophagy. These data suggest that oxidative stress-mediated AMPK/mTOR-dependent autophagy and AMPK/p38-dependent apoptosis could be valid therapeutic targets for neuroprotection. | sr |
dc.language.iso | en | sr |
dc.publisher | Amsterdam: Elsevier | sr |
dc.relation | info:eu-repo/grantAgreement/MESTD/Basic Research (BR or ON)/173053/RS// | sr |
dc.relation | info:eu-repo/grantAgreement/MESTD/Integrated and Interdisciplinary Research (IIR or III)/41025/RS// | sr |
dc.rights | openAccess | sr |
dc.source | Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease | sr |
dc.title | Autophagy-dependent and -independent involvement of AMP-activated protein kinase in 6-hydroxydopamine toxicity to SH-SY5Y neuroblastoma cells | sr |
dc.type | article | sr |
dc.rights.license | ARR | sr |
dc.rights.holder | © 2012 Elsevier B.V. | sr |
dc.citation.issue | 11 | |
dc.citation.volume | 1822 | |
dc.identifier.doi | 10.1016/j.bbadis.2012.08.006. | |
dc.identifier.pmid | 22917563 | |
dc.identifier.scopus | 2-s2.0-84865550601 | |
dc.identifier.wos | 000309566200019 | |
dc.citation.spage | 1826 | |
dc.citation.epage | 1836 | |
dc.type.version | publishedVersion | sr |
dc.identifier.fulltext | https://radar.ibiss.bg.ac.rs/bitstream/id/16134/bitstream_16134.pdf | |
dc.citation.rank | M21 |