Thioredoxin Confers Intrinsic Resistance to Cytostatic Drugs in Human Glioma Cells

Overview

Journal Int J Mol Sci

Publisher MDPI

Specialties Biochemistry
Chemistry
Molecular Biology

Date 2018 Sep 26

PMID 30248944

Citations 14

Authors

Bodo Haas

Lena Schutte

Maria Wos-Maganga

Sandra Weickhardt

Marco Timmer

Niels Eckstein

Affiliations

Soon will be listed here.

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.

Citing Articles

Exploring the Role of Thioredoxin system in Cancer Immunotherapy.

Sun L, Yu A, Yang Y, Wang Z, Wang W, Luo L J Cancer. 2025; 16(1):66-80.

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Synergistic Dual Targeting of Thioredoxin and Glutathione Systems Irrespective of p53 in Glioblastoma Stem Cells.

Jamali F, Lan K, Daniel P, Petrecca K, Sabri S, Abdulkarim B Antioxidants (Basel). 2024; 13(10).

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KRAS is a molecular determinant of platinum responsiveness in glioblastoma.

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The role of TXNIP in cancer: a fine balance between redox, metabolic, and immunological tumor control.

Deng J, Pan T, Liu Z, McCarthy C, Vicencio J, Cao L Br J Cancer. 2023; 129(12):1877-1892.

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The Role of the Thioredoxin Detoxification System in Cancer Progression and Resistance.

Jovanovic M, Podolski-Renic A, Krasavin M, Pesic M Front Mol Biosci. 2022; 9:883297.

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References

Welsh S, Bellamy W, Briehl M, Powis G . The redox protein thioredoxin-1 (Trx-1) increases hypoxia-inducible factor 1alpha protein expression: Trx-1 overexpression results in increased vascular endothelial growth factor production and enhanced tumor angiogenesis. Cancer Res. 2002; 62(17):5089-95. View

Oommen D, Yiannakis D, Jha A . BRCA1 deficiency increases the sensitivity of ovarian cancer cells to auranofin. Mutat Res. 2016; 784-785:8-15. DOI: 10.1016/j.mrfmmm.2015.11.002. View

Meuillet E, Mahadevan D, Berggren M, Coon A, Powis G . Thioredoxin-1 binds to the C2 domain of PTEN inhibiting PTEN's lipid phosphatase activity and membrane binding: a mechanism for the functional loss of PTEN's tumor suppressor activity. Arch Biochem Biophys. 2004; 429(2):123-33. DOI: 10.1016/j.abb.2004.04.020. View

Louis D, Perry A, Reifenberger G, von Deimling A, Figarella-Branger D, Cavenee W . The 2016 World Health Organization Classification of Tumors of the Central Nervous System: a summary. Acta Neuropathol. 2016; 131(6):803-20. DOI: 10.1007/s00401-016-1545-1. View

Raninga P, Di Trapani G, Vuckovic S, Bhatia M, Tonissen K . Inhibition of thioredoxin 1 leads to apoptosis in drug-resistant multiple myeloma. Oncotarget. 2015; 6(17):15410-24. PMC: 4558160. DOI: 10.18632/oncotarget.3795. View

Hou G, Liu P, Zhang S, Yang M, Liao J, Yang J . Elimination of stem-like cancer cell side-population by auranofin through modulation of ROS and glycolysis. Cell Death Dis. 2018; 9(2):89. PMC: 5833411. DOI: 10.1038/s41419-017-0159-4. View

Long J, Manchandia T, Ban K, Gao S, Miller C, Chandra J . Adaphostin cytoxicity in glioblastoma cells is ROS-dependent and is accompanied by upregulation of heme oxygenase-1. Cancer Chemother Pharmacol. 2006; 59(4):527-35. DOI: 10.1007/s00280-006-0295-5. View

Carrasco-Garcia E, Saceda M, Martinez-Lacaci I . Role of receptor tyrosine kinases and their ligands in glioblastoma. Cells. 2014; 3(2):199-235. PMC: 4092852. DOI: 10.3390/cells3020199. View

Kim T, Lee S, Kim J, Kim S, Min J, Bae K . Kallikrein-related peptidase 6 induces chemotherapeutic resistance by attenuating auranofin-induced cell death through activation of autophagy in gastric cancer. Oncotarget. 2016; 7(51):85332-85348. PMC: 5356740. DOI: 10.18632/oncotarget.13352. View

10.

Raninga P, Di Trapani G, Vuckovic S, Tonissen K . Cross-talk between two antioxidants, thioredoxin reductase and heme oxygenase-1, and therapeutic implications for multiple myeloma. Redox Biol. 2016; 8:175-85. PMC: 4732019. DOI: 10.1016/j.redox.2016.01.007. View

11.

Raninga P, Di Trapani G, Vuckovic S, Tonissen K . TrxR1 inhibition overcomes both hypoxia-induced and acquired bortezomib resistance in multiple myeloma through NF-кβ inhibition. Cell Cycle. 2016; 15(4):559-72. PMC: 5056617. DOI: 10.1080/15384101.2015.1136038. View

12.

Bhatia M, McGrath K, Di Trapani G, Charoentong P, Shah F, King M . The thioredoxin system in breast cancer cell invasion and migration. Redox Biol. 2016; 8:68-78. PMC: 4712318. DOI: 10.1016/j.redox.2015.12.004. View

13.

Powis G, Kirkpatrick D, Angulo M, Baker A . Thioredoxin redox control of cell growth and death and the effects of inhibitors. Chem Biol Interact. 1998; 111-112:23-34. DOI: 10.1016/s0009-2797(97)00148-8. View

14.

Zhang J, Li X, Han X, Liu R, Fang J . Targeting the Thioredoxin System for Cancer Therapy. Trends Pharmacol Sci. 2017; 38(9):794-808. DOI: 10.1016/j.tips.2017.06.001. View

15.

Ray P, Huang B, Tsuji Y . Reactive oxygen species (ROS) homeostasis and redox regulation in cellular signaling. Cell Signal. 2012; 24(5):981-90. PMC: 3454471. DOI: 10.1016/j.cellsig.2012.01.008. View

16.

Nishinaka Y, Nishiyama A, Masutani H, Oka S, Ahsan K, Nakayama Y . Loss of thioredoxin-binding protein-2/vitamin D3 up-regulated protein 1 in human T-cell leukemia virus type I-dependent T-cell transformation: implications for adult T-cell leukemia leukemogenesis. Cancer Res. 2004; 64(4):1287-92. DOI: 10.1158/0008-5472.can-03-0908. View

17.

Zhao H, Wang J, Shao W, Wu C, Chen Z, To S . Recent advances in the use of PI3K inhibitors for glioblastoma multiforme: current preclinical and clinical development. Mol Cancer. 2017; 16(1):100. PMC: 5463420. DOI: 10.1186/s12943-017-0670-3. View

18.

Sharma V, Joseph C, Ghosh S, Agarwal A, Mishra M, Sen E . Kaempferol induces apoptosis in glioblastoma cells through oxidative stress. Mol Cancer Ther. 2007; 6(9):2544-53. DOI: 10.1158/1535-7163.MCT-06-0788. View

19.

Yamada M, Tomida A, Yoshikawa H, Taketani Y, Tsuruo T . Overexpression of thioredoxin does not confer resistance to cisplatin in transfected human ovarian and colon cancer cell lines. Cancer Chemother Pharmacol. 1997; 40(1):31-7. DOI: 10.1007/s002800050621. View

20.

Li H, Hu J, Wu S, Wang L, Cao X, Zhang X . Auranofin-mediated inhibition of PI3K/AKT/mTOR axis and anticancer activity in non-small cell lung cancer cells. Oncotarget. 2015; 7(3):3548-58. PMC: 4823126. DOI: 10.18632/oncotarget.6516. View