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

被引:72
作者
Bai, Fang [1 ,2 ]
Morcos, Faruck [1 ,2 ]
Sohn, Yang-Sung [3 ]
Darash-Yahana, Merav [3 ]
Rezende, Celso O. [4 ]
Lipper, Colin H. [4 ]
Paddock, Mark L. [4 ]
Song, Luhua [5 ]
Luo, Yuting [5 ]
Holt, Sarah H. [5 ]
Tamir, Sagi [3 ]
Theodorakis, Emmanuel A. [4 ]
Jennings, Patricia A. [4 ]
Onuchic, Jose N. [1 ,2 ]
Mittler, Ron [5 ]
Nechushtai, Rachel [3 ,5 ]
机构
[1] Rice Univ, Ctr Theoret Biol Phys, Houston, TX 77005 USA
[2] Rice Univ, Dept Phys, Houston, TX 77005 USA
[3] Hebrew Univ Jerusalem, Alexander Silberman Inst Life Sci, IL-91904 Jerusalem, Israel
[4] Univ Calif San Diego, Dept Chem & Biochem, La Jolla, CA 92093 USA
[5] Univ N Texas, Dept Biol Sci, Denton, TX 76203 USA
基金
美国国家科学基金会; 以色列科学基金会;
关键词
NEET proteins; mitocan; iron-sulfur proteins; mitochondria; rational drug design; DRUGGABLE HOT-SPOTS; MITOCHONDRIA; AUTOPHAGY; CHEMISTRY; REVEALS; MINER1; BCL-2;
D O I
10.1073/pnas.1502960112
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
070301 [无机化学]; 070403 [天体物理学]; 070507 [自然资源与国土空间规划学]; 090105 [作物生产系统与生态工程];
摘要
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.
引用
收藏
页码:3698 / 3703
页数:6
相关论文
共 30 条
[1]
Synthesis and evaluation of caged Garcinia xanthones [J].
Batova, Ayse ;
Lam, Thanh ;
Wascholowski, Veit ;
Yu, Alice L. ;
Giannis, Athanassios ;
Theodorakis, Emmanuel A. .
ORGANIC & BIOMOLECULAR CHEMISTRY, 2007, 5 (03) :494-500
[2]
The Synthetic Caged Garcinia Xanthone Cluvenone Induces Cell Stress and Apoptosis and Has Immune Modulatory Activity [J].
Batova, Ayse ;
Altomare, Diego ;
Chantarasriwong, Oraphin ;
Ohlsen, Kari L. ;
Creek, Kim E. ;
Lin, You-Chin ;
Messersmith, Amy ;
Yu, Alice L. ;
Yu, John ;
Theodorakis, Emmanuel A. .
MOLECULAR CANCER THERAPEUTICS, 2010, 9 (11) :2869-2878
[3]
Mitochondrially targeted anti-cancer agents [J].
Biasutto, Lucia ;
Dong, Lan-Feng ;
Zoratti, Mario ;
Neuzil, Jiri .
MITOCHONDRION, 2010, 10 (06) :670-681
[4]
Fragment-based identification of druggable 'hot spots' of proteins using Fourier domain correlation techniques [J].
Brenke, Ryan ;
Kozakov, Dima ;
Chuang, Gwo-Yu ;
Beglov, Dmitri ;
Hall, David ;
Landon, Melissa R. ;
Mattos, Carla ;
Vajda, Sandor .
BIOINFORMATICS, 2009, 25 (05) :621-627
[5]
Bcl-2-associated autophagy regulator Naf-1 required for maintenance of skeletal muscle [J].
Chang, Natasha C. ;
Mai Nguyen ;
Bourdon, Johanne ;
Risse, Paul-Andre ;
Martin, James ;
Danialou, Gawiyou ;
Rizzuto, Rosario ;
Petrof, Basil J. ;
Shore, Gordon C. .
HUMAN MOLECULAR GENETICS, 2012, 21 (10) :2277-2287
[6]
Antagonism of Beclin 1-dependent autophagy by BCL-2 at the endoplasmic reticulum requires NAF-1 [J].
Chang, Natasha C. ;
Nguyen, Mai ;
Germain, Marc ;
Shore, Gordon C. .
EMBO JOURNAL, 2010, 29 (03) :606-618
[7]
Chemistry and Biology of the Caged Garcinia Xanthones [J].
Chantarasriwong, Oraphin ;
Batova, Ayse ;
Chavasiri, Warinthorn ;
Theodorakis, Emmanuel A. .
CHEMISTRY-A EUROPEAN JOURNAL, 2010, 16 (33) :9944-9962
[8]
Evaluation of the pharmacophoric motif of the caged Garcinia xanthones [J].
Chantarasriwong, Oraphin ;
Cho, Woo Cheal ;
Batova, Ayse ;
Chavasiri, Warinthorn ;
Moore, Curtis ;
Rheingold, Arnold L. ;
Theodorakis, Emmanuel A. .
ORGANIC & BIOMOLECULAR CHEMISTRY, 2009, 7 (23) :4886-4894
[9]
Cisd2 deficiency drives premature aging and causes mitochondria-mediated defects in mice [J].
Chen, Yi-Fan ;
Kao, Cheng-Heng ;
Chen, Ya-Ting ;
Wang, Chih-Hao ;
Wu, Chia-Yu ;
Tsai, Ching-Yen ;
Liu, Fu-Chin ;
Yang, Chu-Wen ;
Wei, Yau-Huei ;
Hsu, Ming-Ta ;
Tsai, Shih-Feng ;
Tsai, Ting-Fen .
GENES & DEVELOPMENT, 2009, 23 (10) :1183-1194
[10]
Crystal Structure of Miner1: The Redox-active 2Fe-2S Protein Causative in Wolfram Syndrome 2 [J].
Conlan, Andrea R. ;
Axelrod, Herbert L. ;
Cohen, Aina E. ;
Abresch, Edward C. ;
Zuris, John ;
Yee, David ;
Nechushtai, Rachel ;
Jennings, Patricia A. ;
Paddock, Mark L. .
JOURNAL OF MOLECULAR BIOLOGY, 2009, 392 (01) :143-153