The Fe-S cluster-containing NEET proteins mitoNEET and NAF-1 as chemotherapeutic targets in breast cancer.

Abstract

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.

• Authors: Fang Bai, Faruck Morcos, Yang-Sung Sohn, Merav Darash-Yahana, Celso O Rezende, Colin H Lipper, Mark L Paddock, Luhua Song, Yuting Luo, Sarah H Holt, Sagi Tamir, Emmanuel A Theodorakis, Patricia A Jennings, José N Onuchic, Ron Mittler, Rachel Nechushtai
• Journal: Proceedings of the National Academy of Sciences of the United States of America (Proc Natl Acad Sci U S A) Vol. 112 Issue 12 Pg. 3698-703 (Mar 24 2015) ISSN: 1091-6490 [Electronic] United States
• PMID: 25762074 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)

Chemical References

• Antineoplastic Agents
• CISD1 protein, human
• Iron-Sulfur Proteins
• Mitochondrial Proteins
• NAF1 protein, human
• Ribonucleoproteins
• Xanthones
• cluvenone

Topics

• Antineoplastic Agents (pharmacology)
• Breast Neoplasms (chemistry, drug therapy)
• Cell Line, Tumor
• Cell Proliferation
• Cell Survival
• Cluster Analysis
• Drug Design
• Female
• Humans
• Iron-Sulfur Proteins (chemistry)
• MCF-7 Cells
• Mitochondrial Proteins (chemistry)
• Molecular Conformation
• Molecular Docking Simulation
• Molecular Targeted Therapy
• Ribonucleoproteins (chemistry)
• Software
• Xanthones (chemistry)