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Targeting redox homeostasis in rhabdomyosarcoma cells: GSH-depleting agents enhance auranofin-induced cell death.
Cell Death Dis. 2017 10 05; 8(10):e3067.CD

Abstract

Rhabdomyosarcoma (RMS) cells have recently been reported to be sensitive to oxidative stress. Therefore, we investigated whether concomitant inhibition of the two main antioxidant defense pathways, that is, the thioredoxin (TRX) and the glutathione (GSH) systems, presents a new strategy to trigger cell death in RMS. In this study, we discover that GSH-depleting agents, i.e. γ-glutamylcysteine synthetase inhibitor, buthionine sulfoximine (BSO) or the cystine/glutamate antiporter inhibitor erastin (ERA), synergize with thioredoxin reductase (TrxR) inhibitor auranofin (AUR) to induce cell death in RMS cells. Interestingly, AUR causes accumulation of ubiquitinated proteins when combined with BSO or ERA, in line with recent reports showing that AUR inhibits the proteasome besides TrxR. Consistently, AUR/BSO or AUR/ERA cotreatment increases ubiquitination and expression of the short-lived proteins NOXA and MCL-1, accompanied by increased binding of NOXA to MCL-1. Notably, NOXA knockdown significantly rescues RMS cells from AUR/BSO- or AUR/ERA-induced cell death. In addition, AUR acts together with BSO or ERA to stimulate BAX/BAK and caspase activation. Of note, BSO or ERA abolish the AUR-stimulated increase in GSH levels, leading to reduced GSH levels upon cotreatment. Although AUR/BSO or AUR/ERA cotreatment enhances reactive oxygen species (ROS) production, only thiol-containing antioxidants (i.e., N-acetylcysteine (NAC), GSH), but not the non-thiol-containing ROS scavenger α-Tocopherol consistently suppress AUR/BSO- and AUR/ERA-stimulated cell death in both cell lines. Importantly, re-supply of GSH or its precursor NAC completely prevents AUR/ERA- and AUR/BSO-induced accumulation of ubiquitinated proteins, NOXA upregulation and cell death, indicating that GSH depletion rather than ROS production is critical for AUR/BSO- or AUR/ERA-mediated cell death. Thus, by demonstrating that GSH-depleting agents enhance the antitumor activity of AUR, we highlight new treatment options for RMS by targeting the redox homeostasis.

Authors+Show Affiliations

Institute for Experimental Cancer Research in Pediatrics, Goethe-University, Komturstrasse 3a, Frankfurt, Germany.Institute for Experimental Cancer Research in Pediatrics, Goethe-University, Komturstrasse 3a, Frankfurt, Germany.Institute for Experimental Cancer Research in Pediatrics, Goethe-University, Komturstrasse 3a, Frankfurt, Germany.Institute for Experimental Cancer Research in Pediatrics, Goethe-University, Komturstrasse 3a, Frankfurt, Germany. German Cancer Consortium (DKTK), Partner Site Frankfurt, Germany. German Cancer Research Center (DKFZ), Heidelberg, Germany.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

28981107

Citation

Habermann, Karoline Johanna, et al. "Targeting Redox Homeostasis in Rhabdomyosarcoma Cells: GSH-depleting Agents Enhance Auranofin-induced Cell Death." Cell Death & Disease, vol. 8, no. 10, 2017, pp. e3067.
Habermann KJ, Grünewald L, van Wijk S, et al. Targeting redox homeostasis in rhabdomyosarcoma cells: GSH-depleting agents enhance auranofin-induced cell death. Cell Death Dis. 2017;8(10):e3067.
Habermann, K. J., Grünewald, L., van Wijk, S., & Fulda, S. (2017). Targeting redox homeostasis in rhabdomyosarcoma cells: GSH-depleting agents enhance auranofin-induced cell death. Cell Death & Disease, 8(10), e3067. https://doi.org/10.1038/cddis.2017.412
Habermann KJ, et al. Targeting Redox Homeostasis in Rhabdomyosarcoma Cells: GSH-depleting Agents Enhance Auranofin-induced Cell Death. Cell Death Dis. 2017 10 5;8(10):e3067. PubMed PMID: 28981107.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Targeting redox homeostasis in rhabdomyosarcoma cells: GSH-depleting agents enhance auranofin-induced cell death. AU - Habermann,Karoline Johanna, AU - Grünewald,Leon, AU - van Wijk,Sjoerd, AU - Fulda,Simone, Y1 - 2017/10/05/ PY - 2017/05/20/received PY - 2017/07/14/revised PY - 2017/07/18/accepted PY - 2017/10/6/entrez PY - 2017/10/6/pubmed PY - 2018/6/9/medline SP - e3067 EP - e3067 JF - Cell death & disease JO - Cell Death Dis VL - 8 IS - 10 N2 - Rhabdomyosarcoma (RMS) cells have recently been reported to be sensitive to oxidative stress. Therefore, we investigated whether concomitant inhibition of the two main antioxidant defense pathways, that is, the thioredoxin (TRX) and the glutathione (GSH) systems, presents a new strategy to trigger cell death in RMS. In this study, we discover that GSH-depleting agents, i.e. γ-glutamylcysteine synthetase inhibitor, buthionine sulfoximine (BSO) or the cystine/glutamate antiporter inhibitor erastin (ERA), synergize with thioredoxin reductase (TrxR) inhibitor auranofin (AUR) to induce cell death in RMS cells. Interestingly, AUR causes accumulation of ubiquitinated proteins when combined with BSO or ERA, in line with recent reports showing that AUR inhibits the proteasome besides TrxR. Consistently, AUR/BSO or AUR/ERA cotreatment increases ubiquitination and expression of the short-lived proteins NOXA and MCL-1, accompanied by increased binding of NOXA to MCL-1. Notably, NOXA knockdown significantly rescues RMS cells from AUR/BSO- or AUR/ERA-induced cell death. In addition, AUR acts together with BSO or ERA to stimulate BAX/BAK and caspase activation. Of note, BSO or ERA abolish the AUR-stimulated increase in GSH levels, leading to reduced GSH levels upon cotreatment. Although AUR/BSO or AUR/ERA cotreatment enhances reactive oxygen species (ROS) production, only thiol-containing antioxidants (i.e., N-acetylcysteine (NAC), GSH), but not the non-thiol-containing ROS scavenger α-Tocopherol consistently suppress AUR/BSO- and AUR/ERA-stimulated cell death in both cell lines. Importantly, re-supply of GSH or its precursor NAC completely prevents AUR/ERA- and AUR/BSO-induced accumulation of ubiquitinated proteins, NOXA upregulation and cell death, indicating that GSH depletion rather than ROS production is critical for AUR/BSO- or AUR/ERA-mediated cell death. Thus, by demonstrating that GSH-depleting agents enhance the antitumor activity of AUR, we highlight new treatment options for RMS by targeting the redox homeostasis. SN - 2041-4889 UR - https://www.unboundmedicine.com/medline/citation/28981107/Targeting_redox_homeostasis_in_rhabdomyosarcoma_cells:_GSH_depleting_agents_enhance_auranofin_induced_cell_death_ L2 - http://dx.doi.org/10.1038/cddis.2017.412 DB - PRIME DP - Unbound Medicine ER -