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Molecular Mechanisms of Bortezomib Action: Novel Evidence for the miRNA–mRNA Interaction Involvement

Authors
  • Łuczkowska, Karolina1
  • Rogińska, Dorota1
  • Ulańczyk, Zofia1
  • Paczkowska, Edyta1
  • Schmidt, Christian Andreas
  • Machaliński, Bogusław1
  • 1 (E.P.)
Type
Published Article
Journal
International Journal of Molecular Sciences
Publisher
MDPI AG
Publication Date
Jan 05, 2020
Volume
21
Issue
1
Identifiers
DOI: 10.3390/ijms21010350
PMID: 31948068
PMCID: PMC6981510
Source
PubMed Central
Keywords
License
Green

Abstract

Bortezomib is an anti-tumor agent, which inhibits 26S proteasome degrading ubiquitinated proteins. While apoptotic transcription-associated activation in response to bortezomib has been suggested, mechanisms related to its influence on post-transcriptional gene silencing mediated regulation by non-coding RNAs remain not fully elucidated. In the present study, we examined changes in global gene and miRNA expression and analyzed the identified miRNA–mRNA interactions after bortezomib exposure in human neuroblastoma cells to define pathways affected by this agent in this type of cells. Cell viability assays were performed to assess cytotoxicity of bortezomib. Global gene and miRNA expression profiles of neuroblastoma cells after 24-h incubation with bortezomib were determined using genome-wide RNA and miRNA microarray technology. Obtained results were then confirmed by qRT-PCR and Western blot. Further bioinformatical analysis was performed to identify affected biological processes and pathways. In total, 719 genes and 28 miRNAs were downregulated, and 319 genes and 61 miRNAs were upregulated in neuroblastoma cells treated with bortezomib. Possible interactions between dysregulated miRNA/mRNA, which could be linked to bortezomib-induced neurotoxicity, affect neurogenesis, cellular calcium transport, and neuron death. Bortezomib might exert toxic effects on neuroblastoma cells and regulate miRNA–mRNA interactions influencing vital cellular functions. Further studies on the role of specific miRNA–mRNA interactions are needed to elucidate mechanisms of bortezomib action.

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