Regulation of intrinsic prion protein by growth factors and tnf-α: the role of intracellular reactive oxygen species

Function and regulation of the intrinsic prion protein (PrP c) are largely unknown. In the present study the regulation of PrP c expression by growth factors and cytokines that increase intracellular reactive oxygen species (ROS) levels was studied in glioma and neuroblastoma cells grown as multicel...

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Published in:	Free radical biology & medicine Vol. 35; no. 6; pp. 586 - 594
Main Authors:	Sauer, Heinrich, Wefer, Katrin, Vetrugno, Vito, Pocchiari, Maurizio, Gissel, Cornelia, Sachinidis, Agapios, Hescheler, Jürgen, Wartenberg, Maria
Format:	Journal Article
Language:	English
Published:	United States Elsevier Inc 15-09-2003
Subjects:	Adenosine Triphosphate - pharmacology Antioxidants - metabolism Gene Expression Regulation, Neoplastic - drug effects Growth factors Growth Substances - pharmacology Humans Multicellular tumor spheroid NADPH Oxidases - metabolism NADPH-oxidase, Free radicals Prion Prions - genetics Prions - metabolism Reactive oxygen species Reactive Oxygen Species - metabolism Reverse Transcriptase Polymerase Chain Reaction Tumor Cells, Cultured Tumor Necrosis Factor-alpha - pharmacology Tumor necrosis factor-α Reactive oxygen species Prion NADPH-oxidase, Free radicals Tumor necrosis factor-α Growth factors Multicellular tumor spheroid
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Summary:	Function and regulation of the intrinsic prion protein (PrP c) are largely unknown. In the present study the regulation of PrP c expression by growth factors and cytokines that increase intracellular reactive oxygen species (ROS) levels was studied in glioma and neuroblastoma cells grown as multicellular tumor spheroids. PrP c protein was significantly increased when glioma spheroids were treated with either ATP, nerve growth factor (NGF), epidermal growth factor (EGF), or tumor necrosis factor α (TNF-α), whereas mRNA levels as evaluated by Reverse Transcriptase-Polymerase Chain Reaction (RT-PCR) remained unchanged. ATP, NGF, EGF, and TNF-α raised intracellular ROS levels as evaluated using the redox-sensitive fluorescence dye 2′7′-dichlorodihydrofluorescein diacetate (H 2DCFDA). The observed elevation in PrP c was completely abolished in the presence of the free radical scavengers vitamin E and ebselen, as well as following pretreatment with the NADPH-oxidase inhibitor diphenylen iodonium chloride (DPI), indicating that PrP c levels are regulated by intracellular ROS. The correlation of PrP c expression to the intracellular ROS levels was investigated by the use of neuroblastoma cells overexpressing either mutant V210I PrP, or wild-type PrP c. It was observed that the intracellular redox state was significantly reduced in PrP c as well as V210I PrP overexpressing cells as compared to non-transfected cells. Consequently, the observed elevation of ROS following treatment with ATP was completely abolished in PrP overexpressing cells. Our data are in line with the assumption that PrP c plays a role as free radical scavenger and/or sensor molecule for oxidative stress.
Bibliography:	ObjectType-Article-2 SourceType-Scholarly Journals-1 ObjectType-Feature-1 content type line 23 ObjectType-Article-1 ObjectType-Feature-2
ISSN:	0891-5849 1873-4596
DOI:	10.1016/S0891-5849(03)00360-5