title: 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.affiliation: Center for Theoretical Biological Physics and Department of Physics, Rice University, Houston, TX 77005;
authors.forename: Fang
authors.initials: F
authors.lastname: Bai
authors.affiliation: Center for Theoretical Biological Physics and Department of Physics, Rice University, Houston, TX 77005;
authors.forename: Faruck
authors.initials: F
authors.lastname: Morcos
authors.affiliation: The Alexander Silberman Institute of Life Science, Hebrew University of Jerusalem, Edmond J. Safra Campus at Givat Ram, Jerusalem 91904, Israel;
authors.forename: Yang-Sung
authors.initials: YS
authors.lastname: Sohn
authors.affiliation: The Alexander Silberman Institute of Life Science, Hebrew University of Jerusalem, Edmond J. Safra Campus at Givat Ram, Jerusalem 91904, Israel;
authors.forename: Merav
authors.initials: M
authors.lastname: Darash-Yahana
authors.affiliation: Department of Chemistry and Biochemistry, University of California, San Diego, La Jolla, CA 92093; and.
authors.forename: Celso O
authors.initials: CO
authors.lastname: Rezende
authors.affiliation: Department of Chemistry and Biochemistry, University of California, San Diego, La Jolla, CA 92093; and.
authors.forename: Colin H
authors.initials: CH
authors.lastname: Lipper
authors.affiliation: Department of Chemistry and Biochemistry, University of California, San Diego, La Jolla, CA 92093; and.
authors.forename: Mark L
authors.initials: ML
authors.lastname: Paddock
authors.affiliation: Department of Biological Sciences, University of North Texas, Denton, TX 76203.
authors.forename: Luhua
authors.initials: L
authors.lastname: Song
authors.affiliation: Department of Biological Sciences, University of North Texas, Denton, TX 76203.
authors.forename: Yuting
authors.initials: Y
authors.lastname: Luo
authors.affiliation: Department of Biological Sciences, University of North Texas, Denton, TX 76203.
authors.forename: Sarah H
authors.initials: SH
authors.lastname: Holt
authors.affiliation: The Alexander Silberman Institute of Life Science, Hebrew University of Jerusalem, Edmond J. Safra Campus at Givat Ram, Jerusalem 91904, Israel;
authors.forename: Sagi
authors.initials: S
authors.lastname: Tamir
authors.affiliation: Department of Chemistry and Biochemistry, University of California, San Diego, La Jolla, CA 92093; and.
authors.forename: Emmanuel A
authors.initials: EA
authors.lastname: Theodorakis
authors.affiliation: Department of Chemistry and Biochemistry, University of California, San Diego, La Jolla, CA 92093; and pajennings@ucsd.edu jonuchic@rice.edu ron.mittler@unt.edu rachel@vms.huji.ac.il.
authors.forename: Patricia A
authors.initials: PA
authors.lastname: Jennings
authors.affiliation: Center for Theoretical Biological Physics and Department of Physics, Rice University, Houston, TX 77005; pajennings@ucsd.edu jonuchic@rice.edu ron.mittler@unt.edu rachel@vms.huji.ac.il.
authors.forename: José N
authors.initials: JN
authors.lastname: Onuchic
authors.affiliation: Department of Biological Sciences, University of North Texas, Denton, TX 76203 pajennings@ucsd.edu jonuchic@rice.edu ron.mittler@unt.edu rachel@vms.huji.ac.il.
authors.forename: Ron
authors.initials: R
authors.lastname: Mittler
authors.affiliation: The Alexander Silberman Institute of Life Science, Hebrew University of Jerusalem, Edmond J. Safra Campus at Givat Ram, Jerusalem 91904, Israel; Department of Biological Sciences, University of North Texas, Denton, TX 76203 pajennings@ucsd.edu jonuchic@rice.edu ron.mittler@unt.edu rachel@vms.huji.ac.il.
authors.forename: Rachel
authors.initials: R
authors.lastname: Nechushtai
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D001943:Breast Neoplasms / Q000737:chemistry / Q000188:drug therapy*; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002470:Cell Survival; D016000:Cluster Analysis; D015195:Drug Design; D005260:Female; D006801:Humans; D007506:Iron-Sulfur Proteins / Q000737:chemistry; D061986:MCF-7 Cells; D024101:Mitochondrial Proteins / Q000737:chemistry*; D008968:Molecular Conformation; D062105:Molecular Docking Simulation; D058990:Molecular Targeted Therapy; D012261:Ribonucleoproteins / Q000737:chemistry*; D012984:Software; D044004:Xanthones / Q000737:chemistry
chemical_list: D000970:Antineoplastic Agents; C525595:CISD1 protein, human; D007506:Iron-Sulfur Proteins; D024101:Mitochondrial Proteins; C551999:NAF1 protein, human; D012261:Ribonucleoproteins; D044004:Xanthones; C556167:cluvenone
keywords: NEET proteins; iron-sulfur proteins; mitocan; mitochondria; rational drug design