Breast cancer tumorigenicity is dependent on high expression levels of NAF-1 and the lability of its Fe-S clusters.
Iron-sulfur (Fe-S) proteins are thought to play an important role in cancer cells mediating redox reactions, DNA replication, and telomere maintenance. Nutrient-deprivation autophagy factor-1 (NAF-1) is a 2Fe-2S protein associated with the progression of multiple cancer types. It is unique among Fe-S proteins because of its 3Cys-1His cluster coordination structure that allows it to be relatively stable, as well as to transfer its clusters to apo-acceptor proteins. Here, we report that overexpression of NAF-1 in xenograft breast cancer tumors results in a dramatic augmentation in tumor size and aggressiveness and that NAF-1 overexpression enhances the tolerance of cancer cells to oxidative stress. Remarkably, overexpression of a NAF-1 mutant with a single point mutation that stabilizes the NAF-1 cluster, NAF-1(H114C), in xenograft breast cancer tumors results in a dramatic decrease in tumor size that is accompanied by enhanced mitochondrial iron and reactive oxygen accumulation and reduced cellular tolerance to oxidative stress. Furthermore, treating breast cancer cells with pioglitazone that stabilizes the 3Cys-1His cluster of NAF-1 results in a similar effect on mitochondrial iron and reactive oxygen species accumulation. Taken together, our findings point to a key role for the unique 3Cys-1His cluster of NAF-1 in promoting rapid tumor growth through cellular resistance to oxidative stress. Cluster transfer reactions mediated by the overexpressed NAF-1 protein are therefore critical for inducing oxidative stress tolerance in cancer cells, leading to rapid tumor growth, and drugs that stabilize the NAF-1 cluster could be used as part of a treatment strategy for cancers that display high NAF-1 expression.
The Alexander Silberman Institute of Life Science, Hebrew University of Jerusalem, Edmond J. Safra Campus at Givat Ram, Jerusalem 91904, Israel;
Merav
M
Darash-Yahana
Department of Human Molecular Genetics and Biochemistry, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv 6997801, Israel;
Yair
Y
Pozniak
Center for Theoretical Biological Physics, Department of Physics and Astronomy, Rice University, Houston, TX 77005; Department of Chemistry, Rice University, Houston, TX 77005; Department of Biosciences, Rice University, Houston, TX 77005;
Mingyang
M
Lu
The Alexander Silberman Institute of Life Science, Hebrew University of Jerusalem, Edmond J. Safra Campus at Givat Ram, Jerusalem 91904, Israel;
Yang-Sung
YS
Sohn
The Alexander Silberman Institute of Life Science, Hebrew University of Jerusalem, Edmond J. Safra Campus at Givat Ram, Jerusalem 91904, Israel;
Ola
O
Karmi
The Alexander Silberman Institute of Life Science, Hebrew University of Jerusalem, Edmond J. Safra Campus at Givat Ram, Jerusalem 91904, Israel;
Sagi
S
Tamir
Center for Theoretical Biological Physics, Department of Physics and Astronomy, Rice University, Houston, TX 77005; Department of Chemistry, Rice University, Houston, TX 77005; Department of Biosciences, Rice University, Houston, TX 77005;
Fang
F
Bai
Department of Biological Sciences and BioDiscovery Institute, University of North Texas, Denton TX 76203;
Luhua
L
Song
Department of Chemistry & Biochemistry, University of California at San Diego, La Jolla, CA 92093;
Patricia A
PA
Jennings
The Lautenberg Center for Immunology and Cancer Research, Institute for Medical Research Israel Canada, Hebrew University-Hadassah Medical School, Jerusalem 91120, Israel.
Eli
E
Pikarsky
Department of Human Molecular Genetics and Biochemistry, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv 6997801, Israel;
Tamar
T
Geiger
Center for Theoretical Biological Physics, Department of Physics and Astronomy, Rice University, Houston, TX 77005; Department of Chemistry, Rice University, Houston, TX 77005; Department of Biosciences, Rice University, Houston, TX 77005; jonuchic@rice.edu Ron.Mittler@unt.edu rachel@mail.huji.ac.il.
José N
JN
Onuchic
Department of Biological Sciences and BioDiscovery Institute, University of North Texas, Denton TX 76203; jonuchic@rice.edu Ron.Mittler@unt.edu rachel@mail.huji.ac.il.
Ron
R
Mittler
The Alexander Silberman Institute of Life Science, Hebrew University of Jerusalem, Edmond J. Safra Campus at Givat Ram, Jerusalem 91904, Israel; jonuchic@rice.edu Ron.Mittler@unt.edu rachel@mail.huji.ac.il.
Rachel
R
Nechushtai
D000818:Animals; D014408:Biomarkers, Tumor / Q000378:metabolism; D001943:Breast Neoplasms / Q000378:metabolism* / Q000473:pathology*; D063646:Carcinogenesis / Q000187:drug effects / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D005260:Female; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism; D008658:Inactivation, Metabolic / Q000187:drug effects; D007501:Iron / Q000378:metabolism; D007506:Iron-Sulfur Proteins / Q000378:metabolism*; D008819:Mice, Nude; D008928:Mitochondria / Q000378:metabolism; D009154:Mutation / Q000235:genetics; D018384:Oxidative Stress; D000077205:Pioglitazone; D055550:Protein Stability / Q000187:drug effects; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D012261:Ribonucleoproteins / Q000378:metabolism*; D045162:Thiazolidinediones; D059467:Transcriptome / Q000235:genetics; D023041:Xenograft Model Antitumor Assays
D014408:Biomarkers, Tumor; C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D007506:Iron-Sulfur Proteins; C551999:NAF1 protein, human; D012333:RNA, Messenger; D017382:Reactive Oxygen Species; D012261:Ribonucleoproteins; D045162:Thiazolidinediones; D007501:Iron; D000077205:Pioglitazone
Fe-S; NAF-1; NEET; ROS; cancer