CISD2 expression is a novel marker correlating with pelvic lymph node metastasis and prognosis in patients with early-stage cervical cancer

Liu, Luxin; Xia, Meng; Wang, Jing; Zhang, Weijing; Zhang, Yanna; He, Mian

doi:10.1007/s12032-014-0183-5

Cited by 46 publications

(41 citation statements)

References 44 publications

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“…Enhanced expression of the 2Fe-2S protein NAF-1 is associated with the onset and progression of multiple cancer types (10,11,(14)(15)(16)(17)(18)(19). To determine whether elevated NAF-1 levels play a direct role in tumor development, we stably overexpressed NAF-1 in MDA-MB-231 cells [NAF-1(+)] and generated xenograft tumors in nude mice.…”

Section: Naf-1 Overexpression Results In a Dramatic Augmentation In Xmentioning

confidence: 99%

“…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. Altering NAF-1 cluster lability via different drugs could therefore be used to treat different cancers that depend on NAF-1 overexpression for their proliferation (10,11,(14)(15)(16)(17)(18)(19).…”

Section: Discussionmentioning

confidence: 99%

“…1). Furthermore, they provide a mechanistic foundation for the role of NAF-1 overexpression in multiple cancer types, including breast (10,11), prostate (15), gastric (16), cervical (17), liver (18), and laryngeal cancers (19).…”

Section: Discussionmentioning

confidence: 99%

“…Enhanced expression of NAF-1 or mNT is associated with different cancers, including breast (10,11,14), prostate (15), gastric (16), cervical (17), liver (18), and laryngeal cancer (19). Silencing of mNT or NAF-1 expression in breast (10,11) or gastric (16) cancer cells significantly inhibited cellular proliferation and tumorigenicity, whereas overexpression of mNT in breast (14) or Significance Elevated expression of the iron-sulfur (Fe-S) protein nutrientdeprivation autophagy factor-1 (NAF-1) is associated with the progression of multiple cancer types.…”

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confidence: 99%

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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.

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: Naf-1 Overexpression Results In a Dramatic Augmentation In Xmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

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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.

127

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“…It is involved in longevity [16], and in mice several studies indicated that suppressed expression of cisd2 led to shortened life spans [88]. In human pathologies mNT and NAF-1 were shown to be involved in diabetes and obesity [89, 90], neurodegeneration and cardiovascular abnormalities, and skeletal muscle maintenance [13, 29, 91], they were also implicated in autophagy, apoptosis [18, 21, 23, 92], aging [16, 93] and cancer [22, 23, 90, 94–97]. In addition, NEET proteins are implicated in the rare genetic disease Wolfram Syndrome 2 (WFS-2).…”

Section: Neet Protein Involvement In Diseasesmentioning

confidence: 99%

The unique fold and lability of the [2Fe-2S] clusters of NEET proteins mediate their key functions in health and disease

et al. 2018

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NEET proteins comprise a new class of [2Fe-2S] cluster proteins. In human, three genes encode for NEET proteins: cisd1 encodes mitoNEET (mNT), cisd2 encodes the Nutrient-deprivation autophagy factor-1 (NAF-1) and cisd3 encodes MiNT (Miner2). These recently discovered proteins play key roles in many processes related to normal metabolism and disease. Indeed, NEET proteins are involved in iron, Fe-S, and reactive oxygen homeostasis in cells and play an important role in regulating apoptosis and autophagy. mNT and NAF-1 are homodimeric and reside on the outer mitochondrial membrane. NAF-1 also resides in the membranes of the ER associated mitochondrial membranes (MAM) and the ER. MiNT is a monomer with distinct asymmetry in the molecular surfaces surrounding the clusters. Unlike its paralogs mNT and NAF-1, it resides within the mitochondria. NAF-1 and mNT share similar backbone folds to the plant homodimeric NEET protein (At-NEET), while MiNT’s backbone fold resembles a bacterial MiNT protein. Despite the variation of amino acid composition among these proteins, all NEET proteins retained their unique CDGSH domain harboring their unique 3Cys:1His [2Fe-2S] cluster coordination through evolution. The coordinating exposed His was shown to convey the lability to the NEET proteins’ [2Fe-2S] clusters. In this minireview, we discuss the NEET fold and its structural elements. Special attention is given to the unique lability of the NEETs’ [2Fe-2S] cluster and the implication of the latter to the NEET proteins’ cellular and systemic function in health and disease.Graphical abstract

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CISD2 enhances the chemosensitivity of gastric cancer through the enhancement of 5‐FU‐induced apoptosis and the inhibition of autophagy by AKT/mTOR pathway

et al. 2017

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Gastric cancer (GC) is a prevalent upper gastrointestinal tumor characterized by high morbidity and mortality due to imperfect screening systems and the rapid development of resistance to 5‐fluorouracil (5‐FU). CDGSH iron sulfur domain 2 (CISD2) has been recently regarded as a candidate oncogene in several types of tumors. It is, therefore, necessary to investigate its biological function and clinical significance in gastric cancer. In this study, the down‐regulated expression level of CISD2 in GC compared with adjacent normal tissues was evaluated by quantitative RT‐PCR and Western blotting. An immunohistochemical analysis indicated that CISD2 expression in GC was significantly correlated with age (P = 0.002), Lauren's classification (P = 0.001), and differentiation (P = 0.049). Two cell lines, MKN1 and BGC823, were used to analyze the role of CISD2 in gastric carcinogenesis and response to 5‐FU through CCK‐8 assays, the RT‐CES system, Transwell assays, flow cytometry, and confocal fluorescence microscopy. The overexpression of CISD2 resulted in reduced cellular growth and proliferation, inhibition of metastatic ability, and increased apoptosis. 5‐FU treatment increased endogenous as well as exogenous overexpression of CISD2 in GC cells. Further investigation revealed that CISD2 enhanced sensitivity to 5‐FU via an increase in apoptosis and inhibition of protective autophagy through the activation of the AKT/mTOR pathway. In conclusion, CISD2 is down‐regulated in gastric cancer, and its effects on the inhibition of cellular proliferation, metastatic ability, and increased chemotherapy sensitivity are mediated by antagonism to 5‐FU‐induced autophagy through the AKT/mTOR pathway.

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CISD2 expression is a novel marker correlating with pelvic lymph node metastasis and prognosis in patients with early-stage cervical cancer

Cited by 46 publications

References 44 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

The unique fold and lability of the [2Fe-2S] clusters of NEET proteins mediate their key functions in health and disease

CISD2 enhances the chemosensitivity of gastric cancer through the enhancement of 5‐FU‐induced apoptosis and the inhibition of autophagy by AKT/mTOR pathway

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