Thioredoxin Confers Intrinsic Resistance to Cytostatic Drugs in Human Glioma Cells

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 β-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.

Drug Resistance in Glioblastoma: The Two Faces of Oxidative Stress

“…As such, the overexpression of PRX-1 generated by therapy in GBM, serves as a survival factor and protects against therapy-induced stress (Svendsen et al, 2011 ). The level of expression of peroxiredoxin-2 (PRX-2) correlated with the resistance to radio- or chemotherapy in GBM (Park et al, 2000 ) and the overexpression of TRX, particularly in the hypoxic region of tumors, contributing to chemotherapy resistance, which was negatively regulated by TRX-interacting protein (TXNIP) (Haas et al, 2018 ). The TXNIP level is directly correlated with patient survival in GBM (Zhang et al, 2017 ), and increasing levels of TRX-1 escalate the scavenging of ROS generated by various anticancer agents (Marks, 2006 ).…”

Natural Sesquiterpene Lactones Enhance Chemosensitivity of Tumor Cells through Redox Regulation of STAT3 Signaling

“…The first ones include superoxide dismutase, catalase, glutathione peroxidase, and glutathione reductase whereas α -tocopherol (vitamin E), β -carotene (vitamin A), ascorbic acid (vitamin C), and uric acid represent the ROS scavenging molecules. Furthermore, multiple and interrelated redox couples, such as NADPH/NADP + , GSH/GSSG, Trx/TrxSS, and cysteine/cystine, contribute to the intracellular redox homeostasis [92–99].…”

Metallothionein-3 promotes cisplatin chemoresistance remodelling in neuroblastoma

“…One important finding was that overexpression of hMT3 in CDDP-sensitive cells induced the up-regulation of thioredoxin (P30048, Q16881 and Q9BRA2) and glutaredoxin (O76003) family proteins, which matches the results found in CDDP-resistant cells. It is known that upregulated thioredoxin and glutaredoxin can be a cause of chemotherapy resistance in various tumour entities 79 , 80 . Another important defence mechanism against ROS is a family of enzymes called superoxide dismutases (SODs).…”