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Small Nucleolar RNAs Determine Resistance to Doxorubicin in Human Osteosarcoma.
Int J Mol Sci. 2020 Jun 24; 21(12)IJ

Abstract

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.

Authors+Show Affiliations

Department of Oncology, University of Torino, 1026 Torino, Italy.Department of Oncology, University of Torino, 1026 Torino, Italy.Department of Oncology, University of Torino, 1026 Torino, Italy.Department of Oncology, University of Torino, 1026 Torino, Italy.Department of Computer Science, University of Torino, 10149 Torino, Italy. Department of Clinical and Biological Sciences, University of Torino, 10043 Orbassano, Italy.Laboratory of Experimental Oncology, Pharmacogenomics and Pharmacogenetics Research Unit, IRCCS Istituto Ortopedico Rizzoli, 40136 Bologna, Italy.Department of Oncology, University of Torino, 1026 Torino, Italy. Candiolo Cancer Institute, FPO-IRCCS, 10060 Candiolo, Italy.Laboratory of Experimental Oncology, Pharmacogenomics and Pharmacogenetics Research Unit, IRCCS Istituto Ortopedico Rizzoli, 40136 Bologna, Italy.Department of Oncology, University of Torino, 1026 Torino, Italy.Department of Computer Science, University of Torino, 10149 Torino, Italy.Department of Oncology, University of Torino, 1026 Torino, Italy.Department of Oncology, University of Torino, 1026 Torino, Italy.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

32599901

Citation

Godel, Martina, et al. "Small Nucleolar RNAs Determine Resistance to Doxorubicin in Human Osteosarcoma." International Journal of Molecular Sciences, vol. 21, no. 12, 2020.
Godel M, Morena D, Ananthanarayanan P, et al. Small Nucleolar RNAs Determine Resistance to Doxorubicin in Human Osteosarcoma. Int J Mol Sci. 2020;21(12).
Godel, M., Morena, D., Ananthanarayanan, P., Buondonno, I., Ferrero, G., Hattinger, C. M., Di Nicolantonio, F., Serra, M., Taulli, R., Cordero, F., Riganti, C., & Kopecka, J. (2020). Small Nucleolar RNAs Determine Resistance to Doxorubicin in Human Osteosarcoma. International Journal of Molecular Sciences, 21(12). https://doi.org/10.3390/ijms21124500
Godel M, et al. Small Nucleolar RNAs Determine Resistance to Doxorubicin in Human Osteosarcoma. Int J Mol Sci. 2020 Jun 24;21(12) PubMed PMID: 32599901.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Small Nucleolar RNAs Determine Resistance to Doxorubicin in Human Osteosarcoma. AU - Godel,Martina, AU - Morena,Deborah, AU - Ananthanarayanan,Preeta, AU - Buondonno,Ilaria, AU - Ferrero,Giulio, AU - Hattinger,Claudia M, AU - Di Nicolantonio,Federica, AU - Serra,Massimo, AU - Taulli,Riccardo, AU - Cordero,Francesca, AU - Riganti,Chiara, AU - Kopecka,Joanna, Y1 - 2020/06/24/ PY - 2020/05/31/received PY - 2020/06/19/revised PY - 2020/06/21/accepted PY - 2020/7/1/entrez PY - 2020/7/1/pubmed PY - 2020/7/1/medline KW - chemoresistance KW - doxorubicin KW - osteosarcoma KW - small nucleolar RNAs JF - International journal of molecular sciences JO - Int J Mol Sci VL - 21 IS - 12 N2 - 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. SN - 1422-0067 UR - https://www.unboundmedicine.com/medline/citation/32599901/Small_Nucleolar_RNAs_Determine_Resistance_to_Doxorubicin_in_Human_Osteosarcoma L2 - https://www.mdpi.com/resolver?pii=ijms21124500 DB - PRIME DP - Unbound Medicine ER -
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