Caspase-dependent Proteolysis of Human Ribonucleotide Reductase Small Subunits R2 and p53R2 during Apoptosis

Tebbi, Ali; Guittet, Olivier; Tuphile, Karine; Cabrié, Aimeric; Lepoivre, Michel

doi:10.1074/jbc.m115.649640

Cited by 10 publications

(3 citation statements)

References 33 publications

(41 reference statements)

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“…Cisplatinum is a chemotherapy agent that forms a platinum complex, and once it enters the cell, binds to DNA, which causes DNA crosslinks as well as oxidative stress and causes cells to undergo apoptosis [ 35 , 36 ]. Cleaved caspase-3 is an apoptotic marker and plays a key role in apoptotic cell death [ 37 ]. The combination of NCe-FA and cisplatinum had the highest caspase-3 among all of the groups (Fig.…”

Section: Resultsmentioning

confidence: 99%

Folic acid tagged nanoceria as a novel therapeutic agent in ovarian cancer

et al. 2016

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BackgroundNanomedicine is a very promising field and nanomedical drugs have recently been used as therapeutic agents against cancer. In a previous study, we showed that Nanoceria (NCe), nanoparticles of cerium oxide, significantly inhibited production of reactive oxygen species, cell migration and invasion of ovarian cancer cells in vitro, without affecting cell proliferation and significantly reduced tumor growth in an ovarian cancer xenograft nude model. Increased expression of folate receptor-α, an isoform of membrane-bound folate receptors, has been described in ovarian cancer. To enable NCe to specifically target ovarian cancer cells, we conjugated nanoceria to folic acid (NCe-FA). Our aim was to investigate the pre-clinical efficacy of NCe-FA alone and in combination with Cisplatin.MethodsOvarian cancer cell lines were treated with NCe or NCe-FA. Cell viability was assessed by MTT and colony forming units. In vivo studies were carried in A2780 generated mouse xenografts treated with 0.1 mg/Kg NCe, 0.1 mg/Kg; NCe-FA and cisplatinum, 4 mg/Kg by intra-peritoneal injections. Tumor weights and burden scores were determined. Immunohistochemistry and toxicity assays were used to evaluate treatment effects.ResultsWe show that folic acid conjugation of NCe increased the cellular NCe internalization and inhibited cell proliferation. Mice treated with NCe-FA had a lower tumor burden compared to NCe, without any vital organ toxicity. Combination of NCe-FA with cisplatinum decreased the tumor burden more significantly. Moreover, NCe-FA was also effective in reducing proliferation and angiogenesis in the xenograft mouse model.ConclusionThus, specific targeting of ovarian cancer cells by NCe-FA holds great potential as an effective therapeutic alone or in combination with standard chemotherapy.Electronic supplementary materialThe online version of this article (doi:10.1186/s12885-016-2206-4) contains supplementary material, which is available to authorized users.

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Section: Resultsmentioning

confidence: 99%

Folic acid tagged nanoceria as a novel therapeutic agent in ovarian cancer

et al. 2016

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“…Data for the RRM2B interaction network was downloaded from the BioGRID database ( Oughtred et al, 2019 ) (10/25/2018) and analyzed by Cytoscape v. 3.6.1 ( Shannon et al, 2003 ). Several interactions were added manually based on literature findings [RRM2B-FOXO3 ( Cho et al, 2014 ), RRM2B-P21 ( Xue et al, 2007 ), RRM2B-TP73 ( Tebbi et al, 2015 ), RRM2B-E2F1 ( Qi et al, 2015 ), RRM2B-MEK2 ( Piao et al, 2012 )]. WebGestalt (WEB-based GEne SeT AnaLysis Toolkit) was used for gene set enrichment analysis to extract biological insights from the genes of interest ( Liao et al, 2019 ).…”

Section: Methodsmentioning

confidence: 99%

RRM2B Is Frequently Amplified Across Multiple Tumor Types: Implications for DNA Repair, Cellular Survival, and Cancer Therapy

et al. 2021

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RRM2B plays a crucial role in DNA replication, repair and oxidative stress. While germline RRM2B mutations have been implicated in mitochondrial disorders, its relevance to cancer has not been established. Here, using TCGA studies, we investigated RRM2B alterations in cancer. We found that RRM2B is highly amplified in multiple tumor types, particularly in MYC-amplified tumors, and is associated with increased RRM2B mRNA expression. We also observed that the chromosomal region 8q22.3–8q24, is amplified in multiple tumors, and includes RRM2B, MYC along with several other cancer-associated genes. An analysis of genes within this 8q-amplicon showed that cancers that have both RRM2B-amplified along with MYC have a distinct pattern of amplification compared to cancers that are unaltered or those that have amplifications in RRM2B or MYC only. Investigation of curated biological interactions revealed that gene products of the amplified 8q22.3–8q24 region have important roles in DNA repair, DNA damage response, oxygen sensing, and apoptosis pathways and interact functionally. Notably, RRM2B-amplified cancers are characterized by mutation signatures of defective DNA repair and oxidative stress, and at least RRM2B-amplified breast cancers are associated with poor clinical outcome. These data suggest alterations in RR2MB and possibly the interacting 8q-proteins could have a profound effect on regulatory pathways such as DNA repair and cellular survival, highlighting therapeutic opportunities in these cancers.

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“…Data for the RRM2B interaction network was downloaded from the BioGRID database [72] (10/25/2018) and analyzed by Cytoscape v. 3.6.1 [73]. Several interactions were added manually based on literature findings (RRM2B-FOXO3 [34], RRM2B-P21 [32], RRM2B-TP73 [74], RRM2B-E2F1 [33], RRM2B-MEK2 [75]).…”

Section: Interaction and Pathway Enrichment Analysismentioning

confidence: 99%

RRM2Bis frequently amplified across multiple tumor types: non-oncogenic addiction and therapeutic opportunities

Iqbal

Demidova

Serrao

et al. 2020

Preprint

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RRM2B plays a crucial role in DNA replication, repair and oxidative stress. While germline RRM2B mutations have been implicated in mitochondrial disorders, its relevance to cancer has not been established. Here, using TCGA data, we investigated RRM2B alterations in cancer. We found that RRM2B is highly amplified in multiple tumor types, particularly in MYC-amplified tumors, and is associated with increased RRM2B mRNA expression. We also observed that the chromosomal region 8q22.3–8q24, is amplified in multiple tumors, and includes RRM2B, MYC along with several other cancer-associated genes. An analysis of genes within this 8q-amplicon showed that cases that have both RRM2B-amplified along with MYC have a distinct pattern of amplification compared to unaltered cases or cases that have amplifications in RRM2B or MYC only. These other 8q-proteins were shown to interact functionally within the RRM2B network of DNA repair, hypoxia and apoptosis regulating proteins. Notably, RRM2B-amplified tumors are characterized by mutation signatures of defective DNA repair and oxidative stress, and in some cancers also associated with poor clinical outcome. These findings suggest that some cancers may require RRM2B for cellular survival, providing novel therapeutic opportunities in these cancers.

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Caspase-dependent Proteolysis of Human Ribonucleotide Reductase Small Subunits R2 and p53R2 during Apoptosis

Cited by 10 publications

References 33 publications

Folic acid tagged nanoceria as a novel therapeutic agent in ovarian cancer

Folic acid tagged nanoceria as a novel therapeutic agent in ovarian cancer

RRM2B Is Frequently Amplified Across Multiple Tumor Types: Implications for DNA Repair, Cellular Survival, and Cancer Therapy

RRM2Bis frequently amplified across multiple tumor types: non-oncogenic addiction and therapeutic opportunities

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