title: NAF-1 and mitoNEET are central to human breast cancer proliferation by maintaining mitochondrial homeostasis and promoting tumor growth.
abstract: Mitochondria are emerging as important players in the transformation process of cells, maintaining the biosynthetic and energetic capacities of cancer cells and serving as one of the primary sites of apoptosis and autophagy regulation. Although several avenues of cancer therapy have focused on mitochondria, progress in developing mitochondria-targeting anticancer drugs nonetheless has been slow, owing to the limited number of known mitochondrial target proteins that link metabolism with autophagy or cell death. Recent studies have demonstrated that two members of the newly discovered family of NEET proteins, NAF-1 (CISD2) and mitoNEET (mNT; CISD1), could play such a role in cancer cells. NAF-1 was shown to be a key player in regulating autophagy, and mNT was proposed to mediate iron and reactive oxygen homeostasis in mitochondria. Here we show that the protein levels of NAF-1 and mNT are elevated in human epithelial breast cancer cells, and that suppressing the level of these proteins using shRNA results in significantly reduced cell proliferation and tumor growth, decreased mitochondrial performance, uncontrolled accumulation of iron and reactive oxygen in mitochondria, and activation of autophagy. Our findings highlight NEET proteins as promising mitochondrial targets for cancer therapy.
authors: Alexander Silberman Institute of Life Science, Hebrew University of Jerusalem, Edmond J. Safra Campus at Givat Ram, Jerusalem 91904, Israel.
authors: Yang-Sung
authors: YS
authors: Sohn
authors: Sagi
authors: S
authors: Tamir
authors: Luhua
authors: L
authors: Song
authors: Dorit
authors: D
authors: Michaeli
authors: Imad
authors: I
authors: Matouk
authors: Andrea R
authors: AR
authors: Conlan
authors: Yael
authors: Y
authors: Harir
authors: Sarah H
authors: SH
authors: Holt
authors: Vladimir
authors: V
authors: Shulaev
authors: Mark L
authors: ML
authors: Paddock
authors: Abraham
authors: A
authors: Hochberg
authors: Ioav Z
authors: IZ
authors: Cabanchick
authors: José N
authors: JN
authors: Onuchic
authors: Patricia A
authors: PA
authors: Jennings
authors: Rachel
authors: R
authors: Nechushtai
authors: Ron
authors: R
authors: Mittler
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D063646:Carcinogenesis / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002470:Cell Survival / Q000187:drug effects; D005260:Female; D006019:Glycolysis / Q000187:drug effects; D006706:Homeostasis; D006801:Humans; D015151:Immunoblotting; D061986:MCF-7 Cells; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008819:Mice, Nude; D046529:Microscopy, Electron, Transmission; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism* / Q000648:ultrastructure; D024101:Mitochondrial Proteins / Q000235:genetics / Q000378:metabolism*; D009840:Oligomycins / Q000494:pharmacology; D000077205:Pioglitazone; D034622:RNA Interference; D017382:Reactive Oxygen Species / Q000378:metabolism; D045162:Thiazolidinediones / Q000494:pharmacology; D014183:Transplantation, Heterologous; D047368:Tumor Burden / Q000235:genetics
chemical_list: C525595:CISD1 protein, human; C523851:CISD2 protein, human; D008565:Membrane Proteins; D024101:Mitochondrial Proteins; D009840:Oligomycins; D017382:Reactive Oxygen Species; D045162:Thiazolidinediones; D000077205:Pioglitazone
keywords: Cisd1; Cisd2; MCF7; MDA-MB-231; Miner1
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