Dataset Information

Proteomic profile of oxaliplatin treated cell line reveals DNA damage induced nucleolar stress as main response.Proteomic profile of oxaliplatin treated cell line reveals DNA damage induced nucleolar stress as main response

ABSTRACT: Oxaliplatin is a widely used anti-cancer drug. It is part of treatment regimens for colorectal and pancreatic cancers, but it is tested in esophageal, biliary tract, gastric or hepatocellular cancers as well. Contrary to this wide application, there is only limited amount of information about oxaliplatin mechanism and response to treatment. We have performed whole-cell proteomic study to obtain cellular response induced by oxaliplatin. For this purpose we have treated CCRF-CEM cell line by 5xIC50 (29.3 μM) for half-time to caspase activation (240 min). The complex proteomic comparison was done on the treated vs. un-treated cells by high-resolution mass spectrometry. We have identified 4049 proteins in average from three biological replicates. From such pool just 76 proteins were significantly downregulated and 31 proteins upregulated in at least of two replicates. Both upregulated and dowregulated proteins are involved in DNA damage response, which is the most significant effect of platinum drugs. Downregulated proteins are split into three fractions. One fraction was centrosomal proteins or proteins involved in G2/M regulation. Second fraction was RNA processing proteins or proteins of processome of both ribosomal subunits. Downregulation of those proteins shows to ongoing nucleolar stress. Third fraction consisted of several ribosomal proteins. This should be sign of ribosomal stress. Nucleolar and ribosomal stress are stress responses manifesting by nucleolar shrinkage or and by inhibition of ribosomal biogenesis. Cellular response to oxaliplatin is thus DNA damage response, which triggers nucleolar and subsequent ribosomal stress.

INSTRUMENT(S): LTQ Orbitrap Elite

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Cell Suspension Culture, T Cell

SUBMITTER: Tomáš Oždian

LAB HEAD: Marián Hajdúch

PROVIDER: PXD003543 | Pride | 2017-05-11

REPOSITORIES: Pride

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Publications

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

Ozdian Tomas T Holub Dusan D Maceckova Zuzana Z Varanasi Lakshman L Rylova Gabriela G Rehulka Jiri J Vaclavkova Jana J Slavik Hanus H Moudry Pavel P Znojek Pawel P Stankova Jarmila J de Sanctis Juan Bautista JB Hajduch Marian M Dzubak Petr P

Journal of proteomics 20170503

Oxaliplatin is widely used to treat colorectal cancer in both palliative and adjuvant settings. It is also being tested for use in treating hematological, esophageal, biliary tract, pancreatic, gastric, and hepatocellular cancers. Despite its routine clinical use, little is known about the responses it induces in cancer cells. Therefore the whole-cell proteomics study was conducted to characterize the cellular response induced by oxaliplatin. Chemosensitive CCRF-CEM cells were treated with oxali ...[more]

PMID: 28478306

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Project description:The nucleolus is a subnuclear compartment with a key role in ribosome biogenesis and cellular stress responses. These mechanisms are governed by a complex interaction of proteins, including the NOC1 network. This study reveals a novel relationship between NOC1 and MYC transcription factor, known for its key role in controlling ribosomal biogenesis and cell growth and proliferation. Here, we demonstrate that NOC1 functions as a direct target of MYC, as it is transcriptionally induced through a functional MYC-binding E-box sequence in the NOC1 promoter region. Furthermore, interactome analysis reveals that NOC1-complex includes the nucleolar proteins NOC2 and NOC3 and other nucleolar components such as Nucleostemin1 Ns1 and mainly components for the transport of ribosomal subunits and maturation and with components for rRNA processing. In response to MYC, NOC1 expression and localization within the nucleolus significantly increase, suggesting a direct functional link between MYC activity and NOC1 function. Notably, NOC1 over-expression leads to the formation of large nuclear granules and enlarged nucleoli, which co-localize with nucleolar fibrillarin and Ns1. Additionally, we demonstrate that NOC1 expression is necessary for Ns1 nucleolar localization, suggesting a role for NOC1 in maintaining nucleolar structure. Finally, the co-expression of NOC1 and MYC enhances the formation of abnormal structures formed by NOC1 within the nucleolus, outlining another aspect of NOC1 and MYC cooperation in nucleolar dynamics. This study reveals NOC1's interactions with proteins involved in RNA processing, modification, and splicing, such as Ythdc1, Flacc, and spenito. These proteins play key roles in mediating N6-methyladenosine (m6A) methylation of mRNAs. NOC1's potential involvement in coordinating RNA splicing and nuclear mRNA export highlights its significance in regulating gene expression. In summary, our study uncovers novel roles for NOC1 in nucleolar homeostasis and establishes its direct connection with MYC in the network governing nucleolar structure and function. These findings also highlight NOC1's interaction with proteins relevant for RNA processing, modification, and splicing, suggesting a broader role in addition to its control of nucleolar homeostasis, providing new insight into NOC1 function that can be further investigated into its function in regulating cellular growth and proliferation.

Dataset Information

Proteomic profile of oxaliplatin treated cell line reveals DNA damage induced nucleolar stress as main response.Proteomic profile of oxaliplatin treated cell line reveals DNA damage induced nucleolar stress as main response

Publications

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

Similar Datasets

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