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Glutathione transferase mu 2 protects glioblastoma cells against aminochrome toxicity by preventing autophagy and lysosome dysfunction
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Number of Authors: 12
2014 (English)In: Autophagy, ISSN 1554-8627, E-ISSN 1554-8635, Vol. 10, no 4, 618-630 p.Article in journal (Refereed) Published
Abstract [en]

U373MG cells constitutively express glutathione S-transferase mu 2 (GSTM2) and exhibit H-3-dopamine uptake, which is inhibited by 2 mu M of nomifensine and 15 mu M of estradiol. We generated a stable cell line (U373MGsiGST6) expressing an siRNA against GSTM2 that resulted in low GSTM2 expression (26% of wild-type U373MG cells). A significant increase in cell death was observed when U373MGsiGST6 cells were incubated with 50 mu M purified aminochrome (18-fold increase) compared with wild-type cells. The incubation of U373MGsiGST6 cells with 75 mu M aminochrome resulted in the formation of autophagic vacuoles containing undigested cellular components, as determined using transmission electron microscopy. A significant increase in autophagosomes was determined by measuring endogenous LC3-II, a significant decrease in cell death was observed in the presence of bafilomycin A(1), and a significant increase in cell death was observed in the presence of trehalose. A significant increase in LAMP2 immunostaining was observed, a significant decrease in bright red fluorescence of lysosomes with acridine orange was observed, and bafilomycin A(1) pretreatment reduced the loss of lysosome acidity. A significant increase in cell death was observed in the presence of lysosomal protease inhibitors. Aggregation of TUBA/-tubulin (tubulin, ) and SQSTM1 protein accumulation were also observed. Moreover, a significant increase in the number of lipids droplets was observed compared with U373MG cells with normal expression of GSTM2. These results support the notion that GSTM2 is a protective enzyme against aminochrome toxicity in astrocytes and that aminochrome cell death in U373MGsiGST6 cells involves autophagic-lysosomal dysfunction.

Place, publisher, year, edition, pages
2014. Vol. 10, no 4, 618-630 p.
Keyword [en]
autophagy, lysosome dysfunction, Parkinson disease, dopamine, aminochrome, glutathione transferase, siRNA, astrocytes
National Category
Cell Biology Chemical Sciences
Identifiers
URN: urn:nbn:se:su:diva-105232DOI: 10.4161/auto.27720ISI: 000335547800007OAI: oai:DiVA.org:su-105232DiVA: diva2:731689
Note

AuthorCount:12;

Available from: 2014-07-02 Created: 2014-06-24 Last updated: 2017-12-05Bibliographically approved

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Mannervik, Bengt
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Department of Neurochemistry
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