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Small Nucleolar RNAs Determine Resistance to Doxorubicin in Human Osteosarcoma
- Source :
- International Journal of Molecular Sciences, Vol 21, Iss 4500, p 4500 (2020), International Journal of Molecular Sciences, Volume 21, Issue 12
- Publication Year :
- 2020
- Publisher :
- MDPI AG, 2020.
-
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.
- Subjects :
- 0301 basic medicine
Ribosome biogenesis
Apoptosis
lcsh:Chemistry
0302 clinical medicine
Tumor Cells, Cultured
polycyclic compounds
Small nucleolar RNA
Cytotoxicity
lcsh:QH301-705.5
Spectroscopy
Antibiotics, Antineoplastic
Chemistry
chemoresistance
General Medicine
Chemoresistance
Doxorubicin
Osteosarcoma
Small nucleolar RNAs
Computer Science Applications
Gene Expression Regulation, Neoplastic
030220 oncology & carcinogenesis
GADD45A
medicine.drug
small nucleolar RNAs
DNA repair
Bone Neoplasms
macromolecular substances
doxorubicin
Article
Catalysis
Inorganic Chemistry
03 medical and health sciences
osteosarcoma
Biomarkers, Tumor
medicine
Humans
RNA, Small Nucleolar
Physical and Theoretical Chemistry
Molecular Biology
Gene
Cell Proliferation
organic chemicals
Organic Chemistry
technology, industry, and agriculture
medicine.disease
carbohydrates (lipids)
030104 developmental biology
lcsh:Biology (General)
lcsh:QD1-999
Drug Resistance, Neoplasm
Cancer research
Subjects
Details
- Language :
- English
- ISSN :
- 16616596 and 14220067
- Volume :
- 21
- Issue :
- 4500
- Database :
- OpenAIRE
- Journal :
- International Journal of Molecular Sciences
- Accession number :
- edsair.doi.dedup.....452ea283f1ad791336daa5b3da2864ca