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

Bai, Fang; Morcos, Faruck; Sohn, Yang-Sung; Darash-Yahana, Merav; Rezende, Celso O.; Lipper, Colin H.; Paddock, Mark L.; Song, Liang; Luo, Yuting; Holt, Sarah H.; Tamir, Sagi; Theodorakis, Emmanuel A.; Jennings, Patricia A.; Onuchic, José N.; Mittler, Ron; Nechushtai, Rachel

doi:10.1073/pnas.1502960112

Cited by 70 publications

(70 citation statements)

References 30 publications

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“…4 and 5). These findings support our previous report that NAF-1 could be one of the cellular targets of a mitocan that affects its cluster stability and causes an increase in mitochondrial iron and ROS accumulation (33). Taken together, our findings suggest that any drastic change in the lability of the NAF-1 cluster would impair its function in maintaining the levels of iron and ROS in mitochondria under control.…”

Section: Discussionsupporting

confidence: 92%

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Breast cancer tumorigenicity is dependent on high expression levels of NAF-1 and the lability of its Fe-S clusters

Darash-Yahana

Pozniak

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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127

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Iron-sulfur (Fe-S) proteins are thought to play an important role in cancer cells mediating redox reactions, DNA replication, and telomere maintenance. Nutrient-deprivation autophagy factor-1 (NAF-1) is a 2Fe-2S protein associated with the progression of multiple cancer types. It is unique among Fe-S proteins because of its 3Cys-1His cluster coordination structure that allows it to be relatively stable, as well as to transfer its clusters to apo-acceptor proteins. Here, we report that overexpression of NAF-1 in xenograft breast cancer tumors results in a dramatic augmentation in tumor size and aggressiveness and that NAF-1 overexpression enhances the tolerance of cancer cells to oxidative stress. Remarkably, overexpression of a NAF-1 mutant with a single point mutation that stabilizes the NAF-1 cluster, NAF-1(H114C), in xenograft breast cancer tumors results in a dramatic decrease in tumor size that is accompanied by enhanced mitochondrial iron and reactive oxygen accumulation and reduced cellular tolerance to oxidative stress. Furthermore, treating breast cancer cells with pioglitazone that stabilizes the 3Cys-1His cluster of NAF-1 results in a similar effect on mitochondrial iron and reactive oxygen species accumulation. Taken together, our findings point to a key role for the unique 3Cys-1His cluster of NAF-1 in promoting rapid tumor growth through cellular resistance to oxidative stress. Cluster transfer reactions mediated by the overexpressed NAF-1 protein are therefore critical for inducing oxidative stress tolerance in cancer cells, leading to rapid tumor growth, and drugs that stabilize the NAF-1 cluster could be used as part of a treatment strategy for cancers that display high NAF-1 expression.Fe-S | ROS | NEET | cancer | NAF-1

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Section: Discussionsupporting

confidence: 92%

“…The druggable binding site on NAF-1 was identified by a four-step computational scheme in our previous work (33). Based on this finding, the binding of PGZ to NAF-1 was studied by our in-house docking molecular tool iFitDock (details in SI Materials and Methods).…”

Section: Meta-analysis Of Transcriptomics Data From 21 Tn (Er- Pr-mentioning

confidence: 99%

Breast cancer tumorigenicity is dependent on high expression levels of NAF-1 and the lability of its Fe-S clusters

Darash-Yahana

Pozniak

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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127

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“…One important target is the mitochondrion, which undergoes apoptosis under drug treatment (27). MAD28 has recently been shown to inhibit an iron-sulfur cluster binding protein, mitoNEET, on the outer membrane of mitochondria in breast cancer cells (29). MitoNEET is involved in cellular iron homeostasis and various mitochondrial functions (42).…”

Section: Resultsmentioning

confidence: 99%

“…Although the detailed mechanism of action of GBA, CLV, and related compounds has not yet been delineated, several studies indicate that they localize to mitochondria and exhibit their bioactivity by affecting mitochondrial structure and function (27,28). Along these lines, the hydroxylated CLVs MAD28 and MAD44 were recently found to bind to the mitoNEET family of iron-sulfur-containing proteins that are located at the outer mitochondrial membrane (29).…”

mentioning

confidence: 99%

Caged Garcinia Xanthones, a Novel Chemical Scaffold with Potent Antimalarial Activity

Morrisey

et al. 2017

Antimicrob Agents Chemother

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Caged Garcinia xanthones (CGXs) constitute a family of natural products that are produced by tropical/subtropical trees of the genus Garcinia. CGXs have a unique chemical architecture, defined by the presence of a caged scaffold at the C ring of a xanthone moiety, and exhibit a broad range of biological activities. Here we show that synthetic CGXs exhibit antimalarial activity against Plasmodium falciparum, the causative parasite of human malaria, at the intraerythrocytic stages. Their activity can be substantially improved by attaching a triphenylphosphonium group at the A ring of the caged xanthone. Specifically, CR135 and CR142 were found to be highly effective antimalarial inhibitors, with 50% effective concentrations as low as ϳ10 nM. CGXs affect malaria parasites at multiple intraerythrocytic stages, with mature stages (trophozoites and schizonts) being more vulnerable than immature rings. Within hours of CGX treatment, malaria parasites display distinct morphological changes, significant reduction of parasitemia (the percentage of infected red blood cells), and aberrant mitochondrial fragmentation. CGXs do not, however, target the mitochondrial electron transport chain, the target of the drug atovaquone and several preclinical candidates. CGXs are cytotoxic to human HEK293 cells at the low micromolar level, which results in a therapeutic window of around 150-fold for the lead compounds. In summary, we show that CGXs are potent antimalarial compounds with structures distinct from those of previously reported antimalarial inhibitors. Our results highlight the potential to further develop Garcinia natural product derivatives as novel antimalarial agents.

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“…Finally, small molecules targeting mNEET or miner1 have been characterized (22,23) and may be used to treat cancer, diabetes, or other pathological conditions. In this perspective, it is essential to understand fully the cellular functions of mNEET, miner1, and miner2 to determine the effects of such compounds on cellular physiology.…”

Section: Discussionmentioning

confidence: 99%

MitoNEET-dependent formation of intermitochondrial junctions

Vernay

Marchetti

Sabra

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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MitoNEET (mNEET) is a dimeric mitochondrial outer membrane protein implicated in many facets of human pathophysiology, notably diabetes and cancer, but its molecular function remains poorly characterized. In this study, we generated and analyzed mNEET KO cells and found that in these cells the mitochondrial network was disturbed. Analysis of 3D-EM reconstructions and of thin sections revealed that genetic inactivation of mNEET did not affect the size of mitochondria but that the frequency of intermitochondrial junctions was reduced. Loss of mNEET decreased cellular respiration, because of a reduction in the total cellular mitochondrial volume, suggesting that intermitochondrial contacts stabilize individual mitochondria. Reexpression of mNEET in mNEET KO cells restored the WT morphology of the mitochondrial network, and reexpression of a mutant mNEET resistant to oxidative stress increased in addition the resistance of the mitochondrial network to H 2 O 2 -induced fragmentation. Finally, overexpression of mNEET increased strongly intermitochondrial contacts and resulted in the clustering of mitochondria. Our results suggest that mNEET plays a specific role in the formation of intermitochondrial junctions and thus participates in the adaptation of cells to physiological changes and to the control of mitochondrial homeostasis.mitoNEET | CISD1 | mitochondria | intermitochondrial junctions | endoplasmic reticulum

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

Cited by 70 publications

References 30 publications

Breast cancer tumorigenicity is dependent on high expression levels of NAF-1 and the lability of its Fe-S clusters

Breast cancer tumorigenicity is dependent on high expression levels of NAF-1 and the lability of its Fe-S clusters

Caged Garcinia Xanthones, a Novel Chemical Scaffold with Potent Antimalarial Activity

MitoNEET-dependent formation of intermitochondrial junctions

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