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Arsenic trioxide (ATO) influences the gene expression of metallothioneins in human glioblastoma cells
Falnoga, Ingrid (Author), Zelenik, Andreja (Author), Šlejkovec, Zdenka (Author), Tušek-Žnidarič, Magda (Author), Zajc, Irena (Author), Jurković Mlakar, Simona (Author), Marc, Janja (Author)

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Abstract
Arsenic trioxide (As(2)O(3); ATO, TRISENOXŽ) is used to treat patients with refractory or relapsed acute promyelocytic leukaemia while its application fortreatment of solid cancers like glioblastoma is still under evaluation. In the present study, we investigated the interaction of arsenic trioxide with metallothionein (MT) isoforms as a possible (protective response) resistance of glioblastoma cells to arsenic-induced cytotoxicity. Special attention was focused on MT3, the isoform expressed mainly in the brain. MT3 has low metal inducibility, fast metal binding/releasing properties and outstanding neuronalinhibitory activity. The human astrocytoma (glioblastoma) cell line U87 MG was treated with 0.6, 2 and 6-7 ŽM arsenic (equivalent to 0.3, 1 and 3-3.5 ŽM As(2)O(3)) for 12, 24 or 48 h and gene expression for different MT isoforms, namely MT2A, MT1A, MT1F, MT1X, MT1E and MT3, was measured by real time qPCR using SYBR Green I and TaqmanŽ gene expression assays. TfR, 18S rRNA, GAPDH and AB were tested as reference genes, and the last two evaluated to be appropriate in conditions of low (GAPDH) and high (AB) arsenic exposure.The gene expression of MT3 gene was additionally tested and confirmedby restriction enzyme analysis with PvuII. In the given conditions the mRNAs of six MT isoforms were identified in human glioblastoma cell line U87 MG. Depending on arsenic exposure conditions, an increase or decrease of MT gene expression was observed for each isoform, with the highest increase for isoforms MT1X, MT1F and MT2A mRNA (up to 13-fold) and more persistent decreases for MT1A, MT1E and MT3 mRNA. Despite the common assumption of the noninducibility of MT3, the evident MT3 mRNA increase was observed during highAs exposure (up to 4-fold). In conclusion, our results clearly demonstratethe influence of As on MT isoform gene expression. The MT1X, MT1F and MT2A increase could represent brain tumour acquired resistance to As cytotoxicity while the MT3 increase is more enigmatic, with its possible involvement in arsenic-related induction of type II cell death.

Language:English
Keywords:glioblastomi, genska ekspresija, astrocitom, trioksidni arzen
Work type:Not categorized (r6)
Tipology:1.01 - Original Scientific Article
Organization:FFA - Faculty of Pharmacy
Year:2012
Number of pages:str. 331-339
Numbering:Vol. 149, issue 3
UDC:577.2
ISSN on article:0163-4984
DOI:10.1007/s12011-012-9431-8 Link is opened in a new window
COBISS.SI-ID:3238513 Link is opened in a new window
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Downloads:226
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Record is a part of a journal

Title:Biological trace element research
Shortened title:Biol. trace elem. res.
Publisher:Humana Press
ISSN:0163-4984
COBISS.SI-ID:5379847 This link opens in a new window

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