Cargando…

Nucleolar Stress Response via Ribosomal Protein L11 Regulates Topoisomerase Inhibitor Sensitivity of P53-Intact Cancers

Nucleolar stress response is caused by perturbations in ribosome biogenesis, induced by the inhibition of ribosomal RNA processing and synthesis, as well as ribosome assembly. This response induces p53 stabilization and activation via ribosomal protein L11 (RPL11), suppressing tumor progression. How...

Descripción completa

Detalles Bibliográficos
Autores principales: Ishihara, Yuka, Nakamura, Kiyoshiro, Nakagawa, Shunsuke, Okamoto, Yasuhiro, Yamamoto, Masatatsu, Furukawa, Tatsuhiko, Kawahara, Kohichi
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9784028/
https://www.ncbi.nlm.nih.gov/pubmed/36555627
http://dx.doi.org/10.3390/ijms232415986
_version_ 1784857713135583232
author Ishihara, Yuka
Nakamura, Kiyoshiro
Nakagawa, Shunsuke
Okamoto, Yasuhiro
Yamamoto, Masatatsu
Furukawa, Tatsuhiko
Kawahara, Kohichi
author_facet Ishihara, Yuka
Nakamura, Kiyoshiro
Nakagawa, Shunsuke
Okamoto, Yasuhiro
Yamamoto, Masatatsu
Furukawa, Tatsuhiko
Kawahara, Kohichi
author_sort Ishihara, Yuka
collection PubMed
description Nucleolar stress response is caused by perturbations in ribosome biogenesis, induced by the inhibition of ribosomal RNA processing and synthesis, as well as ribosome assembly. This response induces p53 stabilization and activation via ribosomal protein L11 (RPL11), suppressing tumor progression. However, anticancer agents that kill cells via this mechanism, and their relationship with the therapeutic efficiency of these agents, remain largely unknown. Here, we sought to investigate whether topoisomerase inhibitors can induce nucleolar stress response as they reportedly block ribosomal RNA transcription. Using rhabdomyosarcoma and rhabdoid tumor cell lines that are sensitive to the nucleolar stress response, we evaluated whether nucleolar stress response is associated with sensitivity to topoisomerase inhibitors ellipticine, doxorubicin, etoposide, topotecan, and anthracyclines. Cell proliferation assay indicated that small interfering RNA-mediated RPL11 depletion resulted in decreased sensitivity to topoisomerase inhibitors. Furthermore, the expression of p53 and its downstream target proteins via western blotting showed the suppression of p53 pathway activation upon RPL11 knockdown. These results suggest that the sensitivity of cancer cells to topoisomerase inhibitors is regulated by RPL11-mediated nucleolar stress responses. Thus, RPL11 expression may contribute to the prediction of the therapeutic efficacy of topoisomerase inhibitors and increase their therapeutic effect of topoisomerase inhibitors.
format Online
Article
Text
id pubmed-9784028
institution National Center for Biotechnology Information
language English
publishDate 2022
publisher MDPI
record_format MEDLINE/PubMed
spelling pubmed-97840282022-12-24 Nucleolar Stress Response via Ribosomal Protein L11 Regulates Topoisomerase Inhibitor Sensitivity of P53-Intact Cancers Ishihara, Yuka Nakamura, Kiyoshiro Nakagawa, Shunsuke Okamoto, Yasuhiro Yamamoto, Masatatsu Furukawa, Tatsuhiko Kawahara, Kohichi Int J Mol Sci Article Nucleolar stress response is caused by perturbations in ribosome biogenesis, induced by the inhibition of ribosomal RNA processing and synthesis, as well as ribosome assembly. This response induces p53 stabilization and activation via ribosomal protein L11 (RPL11), suppressing tumor progression. However, anticancer agents that kill cells via this mechanism, and their relationship with the therapeutic efficiency of these agents, remain largely unknown. Here, we sought to investigate whether topoisomerase inhibitors can induce nucleolar stress response as they reportedly block ribosomal RNA transcription. Using rhabdomyosarcoma and rhabdoid tumor cell lines that are sensitive to the nucleolar stress response, we evaluated whether nucleolar stress response is associated with sensitivity to topoisomerase inhibitors ellipticine, doxorubicin, etoposide, topotecan, and anthracyclines. Cell proliferation assay indicated that small interfering RNA-mediated RPL11 depletion resulted in decreased sensitivity to topoisomerase inhibitors. Furthermore, the expression of p53 and its downstream target proteins via western blotting showed the suppression of p53 pathway activation upon RPL11 knockdown. These results suggest that the sensitivity of cancer cells to topoisomerase inhibitors is regulated by RPL11-mediated nucleolar stress responses. Thus, RPL11 expression may contribute to the prediction of the therapeutic efficacy of topoisomerase inhibitors and increase their therapeutic effect of topoisomerase inhibitors. MDPI 2022-12-15 /pmc/articles/PMC9784028/ /pubmed/36555627 http://dx.doi.org/10.3390/ijms232415986 Text en © 2022 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Ishihara, Yuka
Nakamura, Kiyoshiro
Nakagawa, Shunsuke
Okamoto, Yasuhiro
Yamamoto, Masatatsu
Furukawa, Tatsuhiko
Kawahara, Kohichi
Nucleolar Stress Response via Ribosomal Protein L11 Regulates Topoisomerase Inhibitor Sensitivity of P53-Intact Cancers
title Nucleolar Stress Response via Ribosomal Protein L11 Regulates Topoisomerase Inhibitor Sensitivity of P53-Intact Cancers
title_full Nucleolar Stress Response via Ribosomal Protein L11 Regulates Topoisomerase Inhibitor Sensitivity of P53-Intact Cancers
title_fullStr Nucleolar Stress Response via Ribosomal Protein L11 Regulates Topoisomerase Inhibitor Sensitivity of P53-Intact Cancers
title_full_unstemmed Nucleolar Stress Response via Ribosomal Protein L11 Regulates Topoisomerase Inhibitor Sensitivity of P53-Intact Cancers
title_short Nucleolar Stress Response via Ribosomal Protein L11 Regulates Topoisomerase Inhibitor Sensitivity of P53-Intact Cancers
title_sort nucleolar stress response via ribosomal protein l11 regulates topoisomerase inhibitor sensitivity of p53-intact cancers
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9784028/
https://www.ncbi.nlm.nih.gov/pubmed/36555627
http://dx.doi.org/10.3390/ijms232415986
work_keys_str_mv AT ishiharayuka nucleolarstressresponseviaribosomalproteinl11regulatestopoisomeraseinhibitorsensitivityofp53intactcancers
AT nakamurakiyoshiro nucleolarstressresponseviaribosomalproteinl11regulatestopoisomeraseinhibitorsensitivityofp53intactcancers
AT nakagawashunsuke nucleolarstressresponseviaribosomalproteinl11regulatestopoisomeraseinhibitorsensitivityofp53intactcancers
AT okamotoyasuhiro nucleolarstressresponseviaribosomalproteinl11regulatestopoisomeraseinhibitorsensitivityofp53intactcancers
AT yamamotomasatatsu nucleolarstressresponseviaribosomalproteinl11regulatestopoisomeraseinhibitorsensitivityofp53intactcancers
AT furukawatatsuhiko nucleolarstressresponseviaribosomalproteinl11regulatestopoisomeraseinhibitorsensitivityofp53intactcancers
AT kawaharakohichi nucleolarstressresponseviaribosomalproteinl11regulatestopoisomeraseinhibitorsensitivityofp53intactcancers