Universität zu Köln

Haas, Bodo ORCID: 0000-0002-1213-3527, Schuette, Lena, Wos-Maganga, Maria, Weickhardt, Sandra, Timmer, Marco and Eckstein, Niels (2018). Thioredoxin Confers Intrinsic Resistance to Cytostatic Drugs in Human Glioma Cells. Int. J. Mol. Sci., 19 (10). BASEL: MDPI. ISSN 1422-0067

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Abstract

Thioredoxin (Trx) overexpression is known to be a cause of chemotherapy resistance in various tumor entities. However, Trx effects on resistance are complex and depend strictly on tissue type. In the present study, we analyzed the impact of the Trx system on intrinsic chemoresistance of human glioblastoma multiforme (GBM) cells to cytostatic drugs. Resistance of GBM cell lines and primary cells to drugs and signaling inhibitors was assessed by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assays. Impact of Trx inhibition on apoptosis was investigated by proteome profiling of a subset of proteins and annexin V apoptosis assays. Trx-interacting protein (TXNIP) was overexpressed by transfection and protein expression was determined by immunoblotting. Pharmacological inhibition of Trx by 1-methyl-2-imidazolyl-disulfide (PX-12) reduced viability of three GBM cell lines, induced expression of active caspase-3, and reduced phosphorylation of AKT-kinase and expression of -catenin. Sensitivity to cisplatin could be restored by both PX-12 and recombinant expression of the upstream Trx inhibitor TXNIP, respectively. In addition, PX-12 also sensitized primary human GBM cells to temozolomide. Combined inhibition of Trx and the phosphatidylinositide 3-kinase (PI3K) pathway resulted in massive cell death. We conclude that the Trx system and the PI3K pathway act as a sequential cascade and could potentially present a new drug target.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Haas, Bodo UNSPECIFIED orcid.org/0000-0002-1213-3527 UNSPECIFIED Schuette, Lena UNSPECIFIED UNSPECIFIED UNSPECIFIED Wos-Maganga, Maria UNSPECIFIED UNSPECIFIED UNSPECIFIED Weickhardt, Sandra UNSPECIFIED UNSPECIFIED UNSPECIFIED Timmer, Marco UNSPECIFIED UNSPECIFIED UNSPECIFIED Eckstein, Niels UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-170777
DOI:	10.3390/ijms19102874
Journal or Publication Title:	Int. J. Mol. Sci.
Volume:	19
Number:	10
Date:	2018
Publisher:	MDPI
Place of Publication:	BASEL
ISSN:	1422-0067
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language CENTRAL-NERVOUS-SYSTEM; OVARIAN-CANCER CELLS; MULTIPLE-MYELOMA; ADJUVANT TEMOZOLOMIDE; GLIOBLASTOMA CELLS; HEME OXYGENASE-1; UP-REGULATION; IN-VITRO; AURANOFIN; APOPTOSIS Multiple languages Biochemistry & Molecular Biology; Chemistry, Multidisciplinary Multiple languages
Refereed:	Yes
URI:	http://kups.ub.uni-koeln.de/id/eprint/17077