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Silencing of SENP2 in Multiple Myeloma Induces Bortezomib Resistance by Activating NF-κB Through the Modulation of IκBα Sumoylation
- Source :
- Scientific Reports, Scientific Reports, Vol 10, Iss 1, Pp 1-10 (2020)
- Publication Year :
- 2020
- Publisher :
- Nature Publishing Group UK, 2020.
-
Abstract
- The proteasome inhibitor bortezomib is the most successfully applied chemotherapeutic drug for treating multiple myeloma. However, its clinical efficacy reduced due to resistance development. The underlying molecular mechanisms of bortezomib resistance are poorly understood. In this study, by combining in silico analysis and sgRNA library based drug resistance screening assay, we identified SENP2 (Sentrin/SUMO-specific proteases-2) as a bortezomib sensitive gene and found its expression highly downregulated in bortezomib resistant multiple myeloma patient’s samples. Furthermore, down regulation of SENP2 in multiple myeloma cell line RPMI8226 alleviated bortezomib induced cell proliferation inhibition and apoptosis, whereas, overexpression of SENP2 sensitized these cells to bortezomib treatment. We further demonstrate that knockdown of SENP2 in RPMI8226 cells increased SUMO2 conjugated IκBα that resulted in the activation of NF-κB. Taken together, we report that silencing of SENP2 and consequent activation of NF-κB through the modulation of IκBα sumoylation as a novel mechanism inducing bortezomib resistance in multiple myeloma.
- Subjects :
- 0301 basic medicine
Cell Survival
SUMO protein
lcsh:Medicine
Down-Regulation
Article
Bortezomib
03 medical and health sciences
chemistry.chemical_compound
0302 clinical medicine
NF-KappaB Inhibitor alpha
immune system diseases
hemic and lymphatic diseases
Cell Line, Tumor
medicine
Gene silencing
Humans
Computer Simulation
lcsh:Science
Tumour-suppressor proteins
Multiple myeloma
Cell Proliferation
Gene knockdown
Multidisciplinary
lcsh:R
NF-kappa B
Sumoylation
NF-κB
Proteases
medicine.disease
Gene Expression Regulation, Neoplastic
IκBα
Cysteine Endopeptidases
030104 developmental biology
chemistry
Drug Resistance, Neoplasm
030220 oncology & carcinogenesis
Proteasome inhibitor
Cancer research
lcsh:Q
Multiple Myeloma
medicine.drug
RNA, Guide, Kinetoplastida
Signal Transduction
Subjects
Details
- Language :
- English
- ISSN :
- 20452322
- Volume :
- 10
- Database :
- OpenAIRE
- Journal :
- Scientific Reports
- Accession number :
- edsair.doi.dedup.....09bb660a8aa47bbe89b0d176df656239