Proteomic profiling reveals DNA damage, nucleolar and ribosomal stress are the main responses to oxaliplatin treatment in cancer cells

Oždian, Tomáš; Holub, Dušan; Macečková, Zuzana; Varanasi, Lakshman; Rylová, Gabriela; Řehulka, Jiří; Václavková, Jana; Slavík, Hanuš; Moudrý, Pavel; Znojek, Paweł; Stanková, Jarmila; Sanctis, Juan B. De; Hajdúch, Marián; Džubák, Petr

doi:10.1016/j.jprot.2017.05.005

Cited by 31 publications

(17 citation statements)

References 82 publications

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“…Similar to the data presented here it was recently shown that some chemotherapeutic agents, exemplified by oxaliplatin, act as anti-cancer drugs not by inducing the DNA damage response pathway, but rather by inducing ribosome biogenesis stress [ 51 ]. In support of this finding, a proteomic profiling revealed that numerous ribosomal proteins are dysregulated in response to oxaliplatin treatment in T-lymphoblastic leukemia-derived cancer cells [ 52 ].…”

Section: Discussionmentioning

confidence: 95%

Identification of differentially expressed genes and pathways in mice exposed to mixed field neutron/photon radiation

et al. 2018

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BackgroundRadiation exposure due to the detonation of an improvised nuclear device remains a major security concern. Radiation from such a device involves a combination of photons and neutrons. Although photons will make the greater contribution to the total dose, neutrons will certainly have an impact on the severity of the exposure as they have high relative biological effectiveness.ResultsWe investigated the gene expression signatures in the blood of mice exposed to 3 Gy x-rays, 0.75 Gy of neutrons, or to mixed field photon/neutron with the neutron fraction contributing 5, 15%, or 25% of a total 3 Gy radiation dose. Gene ontology and pathway analysis revealed that genes involved in protein ubiquitination pathways were significantly overrepresented in all radiation doses and qualities. On the other hand, eukaryotic initiation factor 2 (EIF2) signaling pathway was identified as one of the top 10 ranked canonical pathways in neutron, but not pure x-ray, exposures. In addition, the related mTOR and regulation of EIF4/p70S6K pathways were also significantly underrepresented in the exposures with a neutron component, but not in x-ray radiation. The majority of the changed genes in these pathways belonged to the ribosome biogenesis and translation machinery and included several translation initiation factors (e.g. Eif2ak4, Eif3f), as well as 40S and 60S ribosomal subunits (e.g. Rsp19, Rpl19, Rpl27). Many of the differentially downregulated ribosomal genes (e.g. RPS19, RPS28) have been causally associated with human bone marrow failure syndromes and hematologic malignancies. We also observed downregulation of transfer RNA processes, in the neutron-only exposure (p < 0.005). Ingenuity Pathway Analysis (p < 0.05) of differentially expressed genes predicted significantly suppressed activity of the upstream regulators c-Myc and Mycn, transcription factors known to control ribosome biogenesis.ConclusionsWe describe the gene expression profile of mouse blood following exposure to mixed field neutron/photon irradiation. We have discovered that pathways related to protein translation are significantly underrepresented in the exposures containing a neutron component. Our results highlight the significance of neutron exposures that even the smallest percentage can have profound biological effects that will affect medical management and treatment decisions in case of a radiological emergency.Electronic supplementary materialThe online version of this article (10.1186/s12864-018-4884-6) contains supplementary material, which is available to authorized users.

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Section: Discussionmentioning

confidence: 95%

Identification of differentially expressed genes and pathways in mice exposed to mixed field neutron/photon radiation

et al. 2018

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“…Current therapeutic strategies for rectal cancer, include alkylating agents (such as platinum compounds like cisplatin), antimetabolites, and radiotherapy, which mainly induces DNA damage via different modes of action [8,9,10]. Adaption and survival, following treatment with these DNA-damaging agents, also results in increased risk of cancers [11].…”

Section: Introductionmentioning

confidence: 99%

Over-Expression of CHD4 Is an Independent Biomarker of Poor Prognosis in Patients with Rectal Cancers Receiving Concurrent Chemoradiotherapy

Wang

Chou

Yang

et al. 2019

IJMS

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Neoadjuvant concurrent chemoradiotherapy (CCRT), followed by radical proctectomy, is the standard treatment for locally advanced rectal cancer. However, a poor response and therapeutic resistance continue to occur despite this treatment. In this study, we analyzed the microarray datasets (GSE68204) of rectal cancer from the Gene Expression Omnibus database, and identified CHD4 as one of the most significantly up-regulated genes among all subunits of the nucleosome remodeling and histone deacetylation (NuRD) complex, in non-responders to CCRT, among locally advanced rectal cancer (LARC) patients. We confirmed the predictive and prognostic significance of CHD4 expression in CCRT treatment, and its correlation with other clinicopathological features, such as tumor regression grade (TRG), therapeutic response, and patient survival. This was carried out by immunohistochemical studies on endoscopic biopsy tissues from 172 rectal cancer patients, receiving neoadjuvant concurrent chemoradiotherapy (CCRT). A high expression of CHD4 was significantly associated with pre-treatment tumor status (p < 0.001) and lymph node metastasis (p < 0.001), post-treatment tumor status (p < 0.001), and lymph node metastasis (p < 0.001), vascular invasion (p = 0.042), and tumor regression grade (p = 0.001). A high expression of CHD4 could also predict poor disease-specific survival and metastasis-free survival (log-rank test, p = 0.0373 and p < 0.0001, respectively). In multivariate Cox proportional-hazards regression analysis, CHD4 overexpression was an independent factor of poor prognosis for metastasis-free survival (HR, 4.575; 95% CI, 1.717–12.192; p = 0.002). By in vitro studies, based on cell line models, we also demonstrated that, the overexpression of CHD4 induced radio-resistance in microsatellite instability-high (MSI-H) colorectal cells (CRCs). On the contrary, the knockdown of CHD4 enhanced radiosensitivity in microsatellite stable (MSS) CRCs. Altogether, we have identified CHD4 as an important regulator of radio-resistance in both MSI-H and MSS CRC cell lines.

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“…Robust oxaliplatin-induced redistribution of NPM1 has been demonstrated ( 14 , 15 , 16 , 17 ), and it has been shown to inhibit rRNA transcription and induce rearrangement of other nucleolar proteins at low doses (6.25 μM) in human fibrosarcoma cells ( 17 ). Proteomics studies have shown changes in levels of proteins related to ribosome biogenesis upon oxaliplatin treatment ( 18 ). However, in that study it was concluded that nucleolar stress was a consequence of DNA damage.…”

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confidence: 99%

Early nucleolar responses differentiate mechanisms of cell death induced by oxaliplatin and cisplatin

Sutton

DeRose

2021

Journal of Biological Chemistry

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Proteomic profiling reveals DNA damage, nucleolar and ribosomal stress are the main responses to oxaliplatin treatment in cancer cells

Cited by 31 publications

References 82 publications

Identification of differentially expressed genes and pathways in mice exposed to mixed field neutron/photon radiation

Identification of differentially expressed genes and pathways in mice exposed to mixed field neutron/photon radiation

Over-Expression of CHD4 Is an Independent Biomarker of Poor Prognosis in Patients with Rectal Cancers Receiving Concurrent Chemoradiotherapy

Early nucleolar responses differentiate mechanisms of cell death induced by oxaliplatin and cisplatin

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