TPX2 is a downstream target of the eIF4A controlled translational program in neuroblastoma Article Swipe
Kaat Durinck
,
Carolina Nunes
,
Sarah-Lee Bekaert
,
Sara Parsa
,
iris Nelen
,
Fien Martens
,
Elisa de Stanchina
,
Ellen Sanders
,
Sara T’Sas
,
Peihua Zhao
,
Fanny Devloed
,
Aline Eggermont
,
Anna Sablina
,
Lisa Depestel
,
Hans-Guido Wendel
·
YOU?
·
· 2024
· Open Access
·
· DOI: https://doi.org/10.21203/rs.3.rs-5318040/v1
YOU?
·
· 2024
· Open Access
·
· DOI: https://doi.org/10.21203/rs.3.rs-5318040/v1
Current therapies for neuroblastoma are often ineffective and survivors suffer from severe long-term therapy related side-effects, underscoring the need for identification of novel drugging strategies. We performed an in-depth evaluation of phenotypic and molecular responses following exposure of neuroblastoma cells to the rocaglate CR-1-31-B, scrutinizing its mode-of-action through integrative ribosome footprinting and shotgun proteome profiling. We could show that CR-1-31-B significantly reduces tumor growth in vivo without apparent toxicity. By means of combined ribosome footprinting and transcriptome analysis we uncovered that CR-1-31-B treatment downregulates translation efficiencies of several major neuroblastoma dependencies including MYCN, CCND1 and ALK as well as factors involved in the G2/M checkpoint. Upregulated targets are enriched for oxidative phosphorylation pathway components and DNA repair. At the proteome level, CR-1-31-B imposed downregulation of a FOXM1 driven signature, including the FOXM1 target gene TPX2. We show that neuroblastoma cells are dependent on TPX2 for growth and DNA repair with knockdown sensitizing tumor cells to pharmacological CHK1 inhibition. In keeping with this finding, we observed synergistic effects of CHK1 inhibition in combination with CR-1-31-B. In conclusion, our data support CR-1-31-B as a potent novel therapeutic agent in neuroblastoma, in particular in combination with DNA damage or replication stress inducing agents.
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Metadata
- Type
- preprint
- Language
- en
- Landing Page
- https://doi.org/10.21203/rs.3.rs-5318040/v1
- https://www.researchsquare.com/article/rs-5318040/latest.pdf
- OA Status
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- Related Works
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- OpenAlex ID
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All OpenAlex metadata
Raw OpenAlex JSON
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https://openalex.org/W4404487491Canonical identifier for this work in OpenAlex
- DOI
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https://doi.org/10.21203/rs.3.rs-5318040/v1Digital Object Identifier
- Title
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TPX2 is a downstream target of the eIF4A controlled translational program in neuroblastomaWork title
- Type
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preprintOpenAlex work type
- Language
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enPrimary language
- Publication year
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2024Year of publication
- Publication date
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2024-11-18Full publication date if available
- Authors
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Kaat Durinck, Carolina Nunes, Sarah-Lee Bekaert, Sara Parsa, iris Nelen, Fien Martens, Elisa de Stanchina, Ellen Sanders, Sara T’Sas, Peihua Zhao, Fanny Devloed, Aline Eggermont, Anna Sablina, Lisa Depestel, Hans-Guido WendelList of authors in order
- Landing page
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https://doi.org/10.21203/rs.3.rs-5318040/v1Publisher landing page
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https://www.researchsquare.com/article/rs-5318040/latest.pdfDirect link to full text PDF
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YesWhether a free full text is available
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goldOpen access status per OpenAlex
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https://www.researchsquare.com/article/rs-5318040/latest.pdfDirect OA link when available
- Concepts
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Downstream (manufacturing), Neuroblastoma, eIF4A, Posttranslational modification, Computer science, Chemistry, Biology, Translation (biology), Business, Biochemistry, Genetics, Marketing, Messenger RNA, Enzyme, Gene, Cell cultureTop concepts (fields/topics) attached by OpenAlex
- Cited by
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0Total citation count in OpenAlex
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10Other works algorithmically related by OpenAlex
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| abstract_inverted_index.could | 57 |
| abstract_inverted_index.major | 89 |
| abstract_inverted_index.means | 71 |
| abstract_inverted_index.novel | 23, 184 |
| abstract_inverted_index.often | 6 |
| abstract_inverted_index.tumor | 63, 153 |
| abstract_inverted_index.damage | 195 |
| abstract_inverted_index.driven | 128 |
| abstract_inverted_index.growth | 64, 146 |
| abstract_inverted_index.level, | 121 |
| abstract_inverted_index.potent | 183 |
| abstract_inverted_index.repair | 149 |
| abstract_inverted_index.severe | 12 |
| abstract_inverted_index.stress | 198 |
| abstract_inverted_index.suffer | 10 |
| abstract_inverted_index.target | 133 |
| abstract_inverted_index.Current | 1 |
| abstract_inverted_index.agents. | 200 |
| abstract_inverted_index.effects | 167 |
| abstract_inverted_index.factors | 100 |
| abstract_inverted_index.imposed | 123 |
| abstract_inverted_index.keeping | 160 |
| abstract_inverted_index.pathway | 113 |
| abstract_inverted_index.reduces | 62 |
| abstract_inverted_index.related | 15 |
| abstract_inverted_index.repair. | 117 |
| abstract_inverted_index.several | 88 |
| abstract_inverted_index.shotgun | 53 |
| abstract_inverted_index.support | 179 |
| abstract_inverted_index.targets | 107 |
| abstract_inverted_index.therapy | 14 |
| abstract_inverted_index.through | 48 |
| abstract_inverted_index.without | 67 |
| abstract_inverted_index.analysis | 78 |
| abstract_inverted_index.apparent | 68 |
| abstract_inverted_index.combined | 73 |
| abstract_inverted_index.drugging | 24 |
| abstract_inverted_index.enriched | 109 |
| abstract_inverted_index.exposure | 37 |
| abstract_inverted_index.finding, | 163 |
| abstract_inverted_index.in-depth | 29 |
| abstract_inverted_index.inducing | 199 |
| abstract_inverted_index.involved | 101 |
| abstract_inverted_index.observed | 165 |
| abstract_inverted_index.proteome | 54, 120 |
| abstract_inverted_index.ribosome | 50, 74 |
| abstract_inverted_index.CR-1-31-B | 60, 82, 122, 180 |
| abstract_inverted_index.dependent | 142 |
| abstract_inverted_index.following | 36 |
| abstract_inverted_index.including | 92, 130 |
| abstract_inverted_index.knockdown | 151 |
| abstract_inverted_index.long-term | 13 |
| abstract_inverted_index.molecular | 34 |
| abstract_inverted_index.oxidative | 111 |
| abstract_inverted_index.performed | 27 |
| abstract_inverted_index.responses | 35 |
| abstract_inverted_index.rocaglate | 43 |
| abstract_inverted_index.survivors | 9 |
| abstract_inverted_index.therapies | 2 |
| abstract_inverted_index.toxicity. | 69 |
| abstract_inverted_index.treatment | 83 |
| abstract_inverted_index.uncovered | 80 |
| abstract_inverted_index.CR-1-31-B, | 44 |
| abstract_inverted_index.CR-1-31-B. | 174 |
| abstract_inverted_index.components | 114 |
| abstract_inverted_index.evaluation | 30 |
| abstract_inverted_index.inhibition | 170 |
| abstract_inverted_index.particular | 190 |
| abstract_inverted_index.phenotypic | 32 |
| abstract_inverted_index.profiling. | 55 |
| abstract_inverted_index.signature, | 129 |
| abstract_inverted_index.Upregulated | 106 |
| abstract_inverted_index.checkpoint. | 105 |
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| abstract_inverted_index.conclusion, | 176 |
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| abstract_inverted_index.inhibition. | 158 |
| abstract_inverted_index.integrative | 49 |
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| abstract_inverted_index.sensitizing | 152 |
| abstract_inverted_index.strategies. | 25 |
| abstract_inverted_index.synergistic | 166 |
| abstract_inverted_index.therapeutic | 185 |
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| abstract_inverted_index.dependencies | 91 |
| abstract_inverted_index.efficiencies | 86 |
| abstract_inverted_index.footprinting | 51, 75 |
| abstract_inverted_index.scrutinizing | 45 |
| abstract_inverted_index.underscoring | 17 |
| abstract_inverted_index.downregulates | 84 |
| abstract_inverted_index.neuroblastoma | 4, 39, 90, 139 |
| abstract_inverted_index.side-effects, | 16 |
| abstract_inverted_index.significantly | 61 |
| abstract_inverted_index.transcriptome | 77 |
| abstract_inverted_index.downregulation | 124 |
| abstract_inverted_index.identification | 21 |
| abstract_inverted_index.mode-of-action | 47 |
| abstract_inverted_index.neuroblastoma, | 188 |
| abstract_inverted_index.pharmacological | 156 |
| abstract_inverted_index.phosphorylation | 112 |
| abstract_inverted_index.<title>Abstract</title> | 0 |
| cited_by_percentile_year | |
| countries_distinct_count | 2 |
| institutions_distinct_count | 15 |
| sustainable_development_goals[0].id | https://metadata.un.org/sdg/3 |
| sustainable_development_goals[0].score | 0.8399999737739563 |
| sustainable_development_goals[0].display_name | Good health and well-being |
| citation_normalized_percentile.value | 0.36304998 |
| citation_normalized_percentile.is_in_top_1_percent | False |
| citation_normalized_percentile.is_in_top_10_percent | False |