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

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

Research output: Contribution to journalArticlepeer-review

64 Scopus citations

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.

Original languageAmerican English
Pages (from-to)3698-3703
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume112
Issue number12
DOIs
StatePublished - 24 Mar 2015

Bibliographical note

Publisher Copyright:
© 2015, National Academy of Sciences. All rights reserved.

Keywords

  • Iron-sulfur proteins
  • Mitocan
  • Mitochondria
  • Neet proteins
  • Rational drug design

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