Redox signals at the ER-mitochondria interface control melanoma progression

2019 | journal article; research paper. A publication with affiliation to the University of Göttingen.

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​Redox signals at the ER-mitochondria interface control melanoma progression​
Zhang, X.; Gibhardt, C. S; Will, T.; Stanisz, H.; Körbel, C.; Mitkovski, M. & Stejerean, I. et al.​ (2019) 
The EMBO Journal38(15) art. e100871​.​ DOI: https://doi.org/10.15252/embj.2018100871 

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Authors
Zhang, Xin; Gibhardt, Christine S; Will, Thorsten; Stanisz, Hedwig; Körbel, Christina; Mitkovski, Miso; Stejerean, Ioana; Cappello, Sabrina; Pacheu-Grau, David; Dudek, Jan; Tahbaz, Nasser; Mina, Lucas; Simmen, Thomas; Laschke, Matthias W; Menger, Michael D; Schön, Michael P; Helms, Volkhard; Niemeyer, Barbara A; Rehling, Peter ; Vultur, Adina; Bogeski, Ivan 
Abstract
Reactive oxygen species (ROS) are emerging as important regulators of cancer growth and metastatic spread. However, how cells integrate redox signals to affect cancer progression is not fully understood. Mitochondria are cellular redox hubs, which are highly regulated by interactions with neighboring organelles. Here, we investigated how ROS at the endoplasmic reticulum (ER)-mitochondria interface are generated and translated to affect melanoma outcome. We show that TMX1 and TMX3 oxidoreductases, which promote ER-mitochondria communication, are upregulated in melanoma cells and patient samples. TMX knockdown altered mitochondrial organization, enhanced bioenergetics, and elevated mitochondrial- and NOX4-derived ROS. The TMX-knockdown-induced oxidative stress suppressed melanoma proliferation, migration, and xenograft tumor growth by inhibiting NFAT1. Furthermore, we identified NFAT1-positive and NFAT1-negative melanoma subgroups, wherein NFAT1 expression correlates with melanoma stage and metastatic potential. Integrative bioinformatics revealed that genes coding for mitochondrial- and redox-related proteins are under NFAT1 control and indicated that TMX1, TMX3, and NFAT1 are associated with poor disease outcome. Our study unravels a novel redox-controlled ER-mitochondria-NFAT1 signaling loop that regulates melanoma pathobiology and provides biomarkers indicative of aggressive disease.
Issue Date
2019
Journal
The EMBO Journal 
Project
SFB 1190: Transportmaschinen und Kontaktstellen zellulärer Kompartimente 
SFB 1190 | P13: Protein Transport über den mitochondrialen Carrier Transportweg 
SFB 1190 | P17: Die Rolle mitochondrialer Kontaktstellen im Rahmen tumorrelevanter Calcium- und Redox-Signalwege 
Working Group
RG Bogeski 
External URL
https://sfb1190.med.uni-goettingen.de/production/literature/publications/80
ISSN
0261-4189; 1460-2075
eISSN
1460-2075
Language
English

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