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Unraveling a mechanism driving poor-prognosis prostate cancer: overexpression of the DNA repair gene, ribonucleotide reductase small subunit M2

ABSTRACT: Unraveling a mechanism driving poor-prognosis prostate cancer: overexpression of the DNA repair gene, ribonucleotide reductase small subunit M2

PROVIDER: PRJNA486989 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR7726350.fastq.gz	Fastqsanger.gz
	SRR7726343.fastq.gz	Fastqsanger.gz
	SRR7726344.fastq.gz	Fastqsanger.gz
	SRR7726345.fastq.gz	Fastqsanger.gz
	SRR7726346.fastq.gz	Fastqsanger.gz

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Unraveling a mechanism driving poor-prognosis prostate cancer: overexpression of the DNA repair gene, ribonucleotide reductase small subunit M2

Project description:FOXM1 activated RRM2 drives poor outcomes in major PC subtype classifications (PCS and PAM50 classifiers),and targeting RRM2 and its key TFs (e.g. FOXM1) abrogate PC progression.

2019-05-01 | GSE118845 | GEO

Targeting ribonucleotide reductase by 3-AP in primary effusion lymphoma

Project description:KSHV is a principal causative agent of primary effusion lymphoma (PEL) which is lacking of effective treatment. Our previous data have showed that HGF/c-MET pathway is highly active within KSHV+ PEL cells and plays important role in tumor cell survival/growth. By using microarray analysis, we have identified the global gene profile controlled by HGF/c-MET pathway within KSHV+ PEL cell-lines and several novel “druggable” candidates closely related to cancer cell survival/growth, including ribonucleotide reductase (RR). We continue to use microarray analysis to identify the gene profile affected within PEL cells exposure to RR inhibitor, 3-AP.

2018-01-01 | GSE91389 | GEO

Ribonucleotide Reductase Subunit Switching in Hepatoblastoma Drug Response and Relapse

Project description:Ribonucleotide Reductase Subunit Switching in Hepatoblastoma Drug Response and Relapse

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Gene expression signature baesd screening identifies ribonucleotide reductase as a candidate therapeutic target in Ewing sarcoma

Project description:There is a critical need in cancer therapeutics to identify targeted therapies that will improve outcomes and decrease toxicities compared to conventional, cytotoxic chemotherapy. Ewing sarcoma is a highly aggressive bone and soft tissue cancer that is caused by the EWS-FLI1 fusion protein. Although EWS-FLI1 is specific for cancer cells, and required for tumorigenesis, directly targeting this transcription factor has proven challenging. Consequently, targeting unique dependencies or key downstream mediators of EWS-FLI1 represent important alternative strategies. We used gene expression data derived from a genetically defined model of Ewing sarcoma to interrogate the Connectivity Map and identify a class of drugs, iron chelators, that downregulate a significant number of EWS-FLI1 target genes. We then identified ribonucleotide reductase M2 (RRM2), the iron-dependent subunit of ribonucleotide reductase (RNR), as one mediator of iron chelator toxicity in Ewing sarcoma cells. Inhibition of RNR in Ewing sarcoma cells led to apoptosis and cell death in vitro and attenuated tumor growth in vivo in a xenograft model. Additionally, we discovered that the sensitivity of Ewing sarcoma cells to inhibition or suppression of RNR is mediated, in part, by high levels of SLFN11, a protein that sensitizes cells to DNA damage. This work demonstrates a unique dependency of Ewing sarcoma cells on RNR and supports further exploration of clinically used inhibitors of RNR as a therapeutic approach in treating this cancer.

2016-12-01 | GSE79641 | GEO

DOPA formation on tyrosine Y150 of Ribonucleotide reductase QSK R2e variant from Gardnerella vaginalis.

Project description:With a crystal structure and mass spectrometry on recombinantly expressed and purified Ribonucleotide reductase QSK R2e variant from Gardnerella vaginalis we show that this protein has a modified DOPA (3,4-Dihydroxy-L-phenylalanine) in the active site analogous to what was observed for the VPK variant. Moreover, we show that this DOPA formation is facilitated by the coexpression of partner proteins NrdI and surprisingly also NrdH and R1 from the same organism.

2023-09-08 | PXD045227 | Pride

Disruption of dNTPs Homeostasis by Ribonucleotide Reductase Hyperactivation Overcomes AML Differentiation Blockade

Project description:Disruption of dNTPs Homeostasis by Ribonucleotide Reductase Hyperactivation Overcomes AML Differentiation Blockade

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Disruption of dNTPs Homeostasis by Ribonucleotide Reductase Hyperactivation Overcomes AML Differentiation Blockade

Project description:Disruption of dNTPs Homeostasis by Ribonucleotide Reductase Hyperactivation Overcomes AML Differentiation Blockade

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A Novel Mechanism Driving Poor-Prognosis Prostate Cancer: Overexpression of the DNA Repair Gene, Ribonucleotide Reductase Small Subunit M2 (RRM2).

Project description:PURPOSE:Defects in genes in the DNA repair pathways significantly contribute to prostate cancer progression. We hypothesize that overexpression of DNA repair genes may also drive poorer outcomes in prostate cancer. The ribonucleotide reductase small subunit M2 (RRM2) is essential for DNA synthesis and DNA repair by producing dNTPs. It is frequently overexpressed in cancers, but very little is known about its function in prostate cancer. EXPERIMENTAL DESIGN:The oncogenic activity of RRM2 in prostate cancer cells was assessed by inhibiting or overexpressing RRM2. The molecular mechanisms of RRM2 function were determined. The clinical significance of RRM2 overexpression was evaluated in 11 prostate cancer clinical cohorts. The efficacy of an RRM2 inhibitor (COH29) was assessed in vitro and in vivo. Finally, the mechanism underlying the transcriptional activation of RRM2 in prostate cancer tissue and cells was determined. RESULTS:Knockdown of RRM2 inhibited its oncogenic function, whereas overexpression of RRM2 promoted epithelial mesenchymal transition in prostate cancer cells. The prognostic value of RRM2 RNA levels in prostate cancer was confirmed in 11 clinical cohorts. Integrating the transcriptomic and phosphoproteomic changes induced by RRM2 unraveled multiple oncogenic pathways downstream of RRM2. Targeting RRM2 with COH29 showed excellent efficacy. Thirteen putative RRM2-targeting transcription factors were bioinformatically identified, and FOXM1 was validated to transcriptionally activate RRM2 in prostate cancer. CONCLUSIONS:We propose that increased expression of RRM2 is a mechanism driving poor patient outcomes in prostate cancer and that its inhibition may be of significant therapeutic value.

| S-EPMC6820162 | biostudies-literature

Disruption of dNTPs Homeostasis by Ribonucleotide Reductase Hyperactivation Overcomes AML Differentiation Blockade II

Project description:Disruption of dNTPs Homeostasis by Ribonucleotide Reductase Hyperactivation Overcomes AML Differentiation Blockade II

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The thioredoxin system determines CHK1 inhibitor sensitivity via redox-mediated regulation of ribonucleotide reductase activity

Project description:Checkpoint kinase 1 (CHK1) is critical for cell survival under replication stress (RS). CHK1 inhibitors (CHK1i’s) in combination with chemotherapy have shown promising results in preclinical studies but have displayed minimal efficacy with substantial toxicity in clinical trials. To explore combinatorial strategies that can overcome these limitations, we perform an unbiased high-throughput screen in a non-small cell lung cancer (NSCLC) cell line and identify thioredoxin1 (Trx1), a major component of the mammalian antioxidant-system, as a determinant of CHK1i sensitivity. We establish a role for redox recycling of RRM1, the larger subunit of ribonucleotide reductase (RNR), and a depletion of the deoxynucleotide pool in this Trx1-mediated CHK1i sensitivity. Further, the TrxR inhibitor auranofin, an approved anti-rheumatoid arthritis drug, shows a synergistic interaction with CHK1i via interruption of the deoxynucleotide pool. Together, we show a pharmacological combination to treat NSCLC that relies on a redox regulatory link between the Trx system and mammalian RNR activity.

2024-04-04 | GSE263176 | GEO

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