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Small Nucleolar RNAs Determine Resistance to Doxorubicin in Human Osteosarcoma

Doxorubicin (Dox) is one of the most important first-line drugs used in osteosarcoma therapy. Multiple and not fully clarified mechanisms, however, determine resistance to Dox. With the aim of identifying new markers associated with Dox-resistance, we found a global up-regulation of small nucleolar...

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Autores principales: Godel, Martina, Morena, Deborah, Ananthanarayanan, Preeta, Buondonno, Ilaria, Ferrero, Giulio, Hattinger, Claudia M., Di Nicolantonio, Federica, Serra, Massimo, Taulli, Riccardo, Cordero, Francesca, Riganti, Chiara, Kopecka, Joanna
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7349977/
https://www.ncbi.nlm.nih.gov/pubmed/32599901
http://dx.doi.org/10.3390/ijms21124500
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author Godel, Martina
Morena, Deborah
Ananthanarayanan, Preeta
Buondonno, Ilaria
Ferrero, Giulio
Hattinger, Claudia M.
Di Nicolantonio, Federica
Serra, Massimo
Taulli, Riccardo
Cordero, Francesca
Riganti, Chiara
Kopecka, Joanna
author_facet Godel, Martina
Morena, Deborah
Ananthanarayanan, Preeta
Buondonno, Ilaria
Ferrero, Giulio
Hattinger, Claudia M.
Di Nicolantonio, Federica
Serra, Massimo
Taulli, Riccardo
Cordero, Francesca
Riganti, Chiara
Kopecka, Joanna
author_sort Godel, Martina
collection PubMed
description Doxorubicin (Dox) is one of the most important first-line drugs used in osteosarcoma therapy. Multiple and not fully clarified mechanisms, however, determine resistance to Dox. With the aim of identifying new markers associated with Dox-resistance, we found a global up-regulation of small nucleolar RNAs (snoRNAs) in human Dox-resistant osteosarcoma cells. We investigated if and how snoRNAs are linked to resistance. After RT-PCR validation of snoRNAs up-regulated in osteosarcoma cells with different degrees of resistance to Dox, we overexpressed them in Dox-sensitive cells. We then evaluated Dox cytotoxicity and changes in genes relevant for osteosarcoma pathogenesis by PCR arrays. SNORD3A, SNORA13 and SNORA28 reduced Dox-cytotoxicity when over-expressed in Dox-sensitive cells. In these cells, GADD45A and MYC were up-regulated, TOP2A was down-regulated. The same profile was detected in cells with acquired resistance to Dox. GADD45A/MYC-silencing and TOP2A-over-expression counteracted the resistance to Dox induced by snoRNAs. We reported for the first time that snoRNAs induce resistance to Dox in human osteosarcoma, by modulating the expression of genes involved in DNA damaging sensing, DNA repair, ribosome biogenesis, and proliferation. Targeting snoRNAs or down-stream genes may open new treatment perspectives in chemoresistant osteosarcomas.
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spelling pubmed-73499772020-07-15 Small Nucleolar RNAs Determine Resistance to Doxorubicin in Human Osteosarcoma Godel, Martina Morena, Deborah Ananthanarayanan, Preeta Buondonno, Ilaria Ferrero, Giulio Hattinger, Claudia M. Di Nicolantonio, Federica Serra, Massimo Taulli, Riccardo Cordero, Francesca Riganti, Chiara Kopecka, Joanna Int J Mol Sci Article Doxorubicin (Dox) is one of the most important first-line drugs used in osteosarcoma therapy. Multiple and not fully clarified mechanisms, however, determine resistance to Dox. With the aim of identifying new markers associated with Dox-resistance, we found a global up-regulation of small nucleolar RNAs (snoRNAs) in human Dox-resistant osteosarcoma cells. We investigated if and how snoRNAs are linked to resistance. After RT-PCR validation of snoRNAs up-regulated in osteosarcoma cells with different degrees of resistance to Dox, we overexpressed them in Dox-sensitive cells. We then evaluated Dox cytotoxicity and changes in genes relevant for osteosarcoma pathogenesis by PCR arrays. SNORD3A, SNORA13 and SNORA28 reduced Dox-cytotoxicity when over-expressed in Dox-sensitive cells. In these cells, GADD45A and MYC were up-regulated, TOP2A was down-regulated. The same profile was detected in cells with acquired resistance to Dox. GADD45A/MYC-silencing and TOP2A-over-expression counteracted the resistance to Dox induced by snoRNAs. We reported for the first time that snoRNAs induce resistance to Dox in human osteosarcoma, by modulating the expression of genes involved in DNA damaging sensing, DNA repair, ribosome biogenesis, and proliferation. Targeting snoRNAs or down-stream genes may open new treatment perspectives in chemoresistant osteosarcomas. MDPI 2020-06-24 /pmc/articles/PMC7349977/ /pubmed/32599901 http://dx.doi.org/10.3390/ijms21124500 Text en © 2020 by the authors. 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 (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Godel, Martina
Morena, Deborah
Ananthanarayanan, Preeta
Buondonno, Ilaria
Ferrero, Giulio
Hattinger, Claudia M.
Di Nicolantonio, Federica
Serra, Massimo
Taulli, Riccardo
Cordero, Francesca
Riganti, Chiara
Kopecka, Joanna
Small Nucleolar RNAs Determine Resistance to Doxorubicin in Human Osteosarcoma
title Small Nucleolar RNAs Determine Resistance to Doxorubicin in Human Osteosarcoma
title_full Small Nucleolar RNAs Determine Resistance to Doxorubicin in Human Osteosarcoma
title_fullStr Small Nucleolar RNAs Determine Resistance to Doxorubicin in Human Osteosarcoma
title_full_unstemmed Small Nucleolar RNAs Determine Resistance to Doxorubicin in Human Osteosarcoma
title_short Small Nucleolar RNAs Determine Resistance to Doxorubicin in Human Osteosarcoma
title_sort small nucleolar rnas determine resistance to doxorubicin in human osteosarcoma
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7349977/
https://www.ncbi.nlm.nih.gov/pubmed/32599901
http://dx.doi.org/10.3390/ijms21124500
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