Breast cancer tumorigenicity is dependent on high expression levels of NAF-1 and the lability of its Fe-S clusters

Merav Darash-Yahana, Yair Pozniak, Mingyang Lu, Yang Sung Sohn, Ola Karmi, Sagi Tamir, Fang Bai, Luhua Song, Patricia A. Jennings, Eli Pikarsky, Tamar Geiger, José N. Onuchic*, Ron Mittler, Rachel Nechushtai

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

59 Scopus citations

Abstract

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.

Original languageAmerican English
Pages (from-to)10890-10895
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume113
Issue number39
DOIs
StatePublished - 27 Sep 2016

Bibliographical note

Funding Information:
This work was supported by Israel Science Foundation Grant 865/13 (to R.N.); the University of North Texas College of Arts and Sciences (R.M.); and the Israel Cancer Research Fund (T.G.). Work at the Center for Theoretical Biological Physics is sponsored by the National Science Foundation (Grants PHY-1427654) and by the Cancer Prevention and Research Institute of Texas (CPRIT) (R1110). M.L. is supported by a training fellowship from the Keck Center for Interdisciplinary Bioscience Training of the Gulf Coast Consortia (CPRIT Grant RP140113); F.B. was partially supported by the Welch Foundation (Grant C-1792); and P.A.J. is supported by National Institutes of Health Grant GM101467.

Keywords

  • Cancer
  • Fe-S
  • NAF-1
  • NEET
  • ROS

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