Identification of ribonucleotide reductase M2 as a potential target for pro-senescence therapy in epithelial ovarian cancer

Aird, Katherine M.; Li, Hua; Xin, Frances; Konstantinopoulos, Panagiotis A.; Zhang, Rugang

doi:10.4161/cc.26953

Cited by 40 publications

(40 citation statements)

References 48 publications

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“…Recent studies from our lab have shown that RRM2 expression is both a prognostic and diagnostic biomarker for melanomas with oncogenic BRAF or NRAS [38] and epithelial ovarian cancer (EOC) [53]. In EOC, RRM2 expression positively correlates with the cell proliferation marker Ki67, tumor grade, and stage [53]. We also observed that high RRM2 expression independently predicts a shorter overall survival in both EOC and melanoma patients [53].…”

Section: Nucleotide Metabolism In Cancermentioning

confidence: 59%

“…In EOC, RRM2 expression positively correlates with the cell proliferation marker Ki67, tumor grade, and stage [53]. We also observed that high RRM2 expression independently predicts a shorter overall survival in both EOC and melanoma patients [53]. [38].…”

Section: Nucleotide Metabolism In Cancermentioning

confidence: 91%

“…These data all point to the presence of a feedback loop whereby the decrease in RRM2 leads to a further decrease in RRM2 through activation of the p53/E2F7 pathway and pRb pathway. Interestingly, senescence of cancer cells such as melanoma and ovarian cancer cells induced by RRM2 inhibition is independent of both p53 and pRB pathway [38, 53]. However, this correlates with activation of the DDR.…”

Section: Role Of Nucleotide Metabolism In Oncogene-induced Senescencementioning

confidence: 99%

“…RRM2 has been shown to be a diagnostic biomarker in colon, breast and pancreas [67–69]. Recent studies from our lab have shown that RRM2 expression is both a prognostic and diagnostic biomarker for melanomas with oncogenic BRAF or NRAS [38] and epithelial ovarian cancer (EOC) [53]. In EOC, RRM2 expression positively correlates with the cell proliferation marker Ki67, tumor grade, and stage [53].…”

Section: Nucleotide Metabolism In Cancermentioning

confidence: 99%

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Nucleotide metabolism, oncogene-induced senescence and cancer

2015

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Senescence is defined as a stable cell growth arrest. Oncogene-induced senescence (OIS) occurs when an activated oncogene is expressed in a normal cell. OIS acts as a bona fide tumor suppressor mechanism by driving stable growth arrest of cancer progenitor cells harboring the initial oncogenic hit. OIS is often characterized by aberrant DNA replication and the associated DNA damage response. Nucleotides, in particular deoxyribonucleotide triphosphates (dNTPs), are necessary for both DNA replication and repair. Imbalanced dNTP pools play a role in a number of human diseases, including during the early stages of cancer development. This review will highlight what is currently known about the role of decreased nucleotide metabolism in OIS, how nucleotide metabolism leads to transformation and tumor progression, and how this pathway can be targeted as a cancer therapeutic by inducing senescence of cancer cells.

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Section: Nucleotide Metabolism In Cancermentioning

confidence: 59%

Section: Nucleotide Metabolism In Cancermentioning

confidence: 91%

Section: Role Of Nucleotide Metabolism In Oncogene-induced Senescencementioning

confidence: 99%

Section: Nucleotide Metabolism In Cancermentioning

confidence: 99%

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Nucleotide metabolism, oncogene-induced senescence and cancer

2015

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“…A role of carbohydrate metabolism for the maintenance of senescence has been established before. 23,24 The main signaling pathways affected were eIF2, S6Kinase and mTOR signaling. All of these pathways regulate cell growth and proliferation.…”

Section: Discussionmentioning

confidence: 99%

Comprehensive analysis of the ubiquitinome during oncogene-induced senescence in human fibroblasts

Bengsch

Tang

et al. 2015

Cell Cycle

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Oncogene-induced senescence (OIS) is an important tumor suppression mechanism preventing uncontrolled proliferation in response to aberrant oncogenic signaling. The profound functional and morphological remodelling of the senescent cell involves extensive changes. In particular, alterations in protein ubiquitination during senescence have not been systematically analyzed previously. Here, we report the first global ubiquitination profile of primary human cells undergoing senescence. We employed a well-characterized in vitro model of OIS, primary human fibroblasts expressing oncogenic RAS. To compare the ubiquitinome of RAS-induced OIS and controls, ubiquitinated peptides were enriched by immune affinity purification and subjected to liquid chromatography tandem mass spectrometry (LC-MS/MS). We identified 4,472 ubiquitination sites, with 397 sites significantly changed (>3 standard deviations) in senescent cells. In addition, we performed mass spectrometry analysis of total proteins in OIS and control cells to account for parallel changes in both protein abundance and ubiquitin levels that did not affect the percentage of ubiquitination of a given protein. Pathway analysis revealed that the OIS-induced ubiquitinome alterations mainly affected 3 signaling networks: eIF2 signaling, eIF4/p70S6K signaling, and mTOR signaling. Interestingly, the majority of the changed ubiquitinated proteins in these pathways belong to the translation machinery. This includes several translation initiation factors (eIF2C2, eIF2B4, eIF3I, eIF3L, eIF4A1) and elongation factors (eEF1G, eEF1A) as well as 40S (RPS4X, RPS7, RPS11 and RPS20) and 60S ribosomal subunits (RPL10, RPL11, RPL18 and RPL35a). In addition, we observed enriched ubiquitination of aminoacyl-tRNA ligases (isoleucyl-, glutamine-, and tyrosine-tRNA ligase), which provide the amino acid-loaded tRNAs for protein synthesis. These results suggest that ubiquitination affects key components of the translation machinery to regulate protein synthesis during OIS. Our results thus point toward ubiquitination as a hitherto unappreciated regulatory mechanism during OIS.

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