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Redox signals at the ER –mitochondria interface control melanoma progression
Author(s) -
Zhang Xin,
Gibhardt Christine S,
Will Thorsten,
Stanisz Hedwig,
Körbel Christina,
Mitkovski Miso,
Stejerean Ioana,
Cappello Sabrina,
PacheuGrau 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
Publication year - 2019
Publication title -
the embo journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 7.484
H-Index - 392
eISSN - 1460-2075
pISSN - 0261-4189
DOI - 10.15252/embj.2018100871
Subject(s) - biology , mitochondrion , redox , microbiology and biotechnology , melanoma , biophysics , biochemistry , cancer research , materials science , metallurgy
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 TMX 1 and TMX 3 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 NOX 4‐derived ROS . The TMX ‐knockdown‐induced oxidative stress suppressed melanoma proliferation, migration, and xenograft tumor growth by inhibiting NFAT 1. Furthermore, we identified NFAT 1‐positive and NFAT 1‐negative melanoma subgroups, wherein NFAT 1 expression correlates with melanoma stage and metastatic potential. Integrative bioinformatics revealed that genes coding for mitochondrial‐ and redox‐related proteins are under NFAT 1 control and indicated that TMX 1, TMX 3, and NFAT 1 are associated with poor disease outcome. Our study unravels a novel redox‐controlled ER –mitochondria– NFAT 1 signaling loop that regulates melanoma pathobiology and provides biomarkers indicative of aggressive disease.