期刊
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
卷 113, 期 39, 页码 10890-10895出版社
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1612736113
关键词
Fe-S; ROS; NEET; cancer; NAF-1
资金
- Israel Science Foundation [865/13]
- University of North Texas College of Arts and Sciences
- Israel Cancer Research Fund
- National Science Foundation [PHY-1427654]
- Cancer Prevention and Research Institute of Texas (CPRIT) [R1110]
- Keck Center for Interdisciplinary Bioscience Training of the Gulf Coast Consortia (CPRIT Grant) [RP140113]
- Welch Foundation [C-1792]
- National Institutes of Health [GM101467]
- Division Of Physics
- Direct For Mathematical & Physical Scien [1427654] Funding Source: National Science Foundation
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(2)S 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, over-expression 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.
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