Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 112, Issue 12, Pages 3698-3703Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1502960112
Keywords
NEET proteins; mitocan; iron-sulfur proteins; mitochondria; rational drug design
Categories
Funding
- Israel Science Foundation (ISF) [865/13]
- University of North Texas College of Arts and Sciences
- Coordination for the Improvement of Higher Education Personnel (CAPES) Foundation-Brazil [12487-12-0]
- NIH [GM101467]
- National Science Foundation [PHY-1427654, MCB-1214457]
- Cancer Prevention and Research Institute of Texas
- Welch Foundation [C-1792]
- Direct For Biological Sciences
- Div Of Molecular and Cellular Bioscience [1214457] Funding Source: National Science Foundation
- Direct For Mathematical & Physical Scien
- Division Of Physics [1308264, 1427654] Funding Source: National Science Foundation
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Identification of novel drug targets and chemotherapeutic agents is a high priority in the fight against cancer. Here, we report that MAD-28, a designed cluvenone (CLV) derivative, binds to and destabilizes two members of a unique class of mitochondrial and endoplasmic reticulum (ER) 2Fe-2S proteins, mitoNEET (mNT) and nutrient-deprivation autophagy factor-1 (NAF-1), recently implicated in cancer cell proliferation. Docking analysis of MAD-28 to mNT/NAF-1 revealed that in contrast to CLV, which formed a hydrogen bond network that stabilized the 2Fe-2S clusters of these proteins, MAD-28 broke the coordinative bond between the His ligand and the cluster's Fe of mNT/NAF-1. Analysis of MAD-28 performed with control (Michigan Cancer Foundation; MCF-10A) and malignant (M.D. Anderson-metastatic breast; MDA-MB-231 or MCF-7) human epithelial breast cells revealed that MAD-28 had a high specificity in the selective killing of cancer cells, without any apparent effects on normal breast cells. MAD-28 was found to target the mitochondria of cancer cells and displayed a surprising similarity in its effects to the effects of mNT/NAF-1 shRNA suppression in cancer cells, causing a decrease in respiration and mitochondrial membrane potential, as well as an increase in mitochondrial iron content and glycolysis. As expected, if the NEET proteins are targets of MAD-28, cancer cells with suppressed levels of NAF-1 or mNT were less susceptible to the drug. Taken together, our results suggest that NEET proteins are a novel class of drug targets in the chemotherapeutic treatment of breast cancer, and that MAD-28 can now be used as a template for rational drug design for NEET Fe-S cluster-destabilizing anticancer drugs.
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