Abstract
Peripheral neuropathy is one of the main side-effects of novel therapeutics used in oncohematological diseases, but the molecular basis underlying its development and progression as well as neurotoxicity mechanisms induced by the use of these therapeutics are still not fully elucidated. The aim of this study was to demonstrate the effect of bortezomib on global gene and miRNA expression on PC12-derived nerve cells. Microarray analysis showed that expression of 1383 genes was downregulated at least two fold and 671 genes were upregulated at least two fold in PC12-derived nerve cells treated with bortezomib compared to untreated/control cells. Analysis of functional annotations mainly identified downregulated processes (e.g., regulation of cell cycle, DNA replication and repair, regulation of cell migration, neuron projection morphogenesis and neurotransmitter secretion). The result of miRNA expression analysis demonstrated only 11 significantly downregulated miRNAs (at least two fold) in bortezomib-treated PC12-derived nerve cells vs. control cells. MiRNAs regulate gene expression, therefore we decided to conduct an analysis comparing the outcomes of miRNA microarray expression data to the obtained mRNA data. The most interesting miRNA–target gene correlation is downregulated expression of miR-130a-3p and miR-152-3p and as a result of this downregulation the expression of the Gadd45 increased. This gene is a member of a group of genes, the transcript expression of which is enhanced after stressful growth arrest conditions and treatment with DNA-damaging agents like drugs or mutagens.
Highlights
Multiple myeloma (MM), which makes up around 10% of all haematological malignancies, is a malignant plasma cell disorder [1]
Microarray analysis showed that expression of 1383 genes was downregulated at least two fold and 671 genes were upregulated at least two fold in PC12-derived nerve cells treated with bortezomib compared to untreated/control cells (Figure 1)
We demonstrated for the first time the global effect of bortezomib on expression of genes and miRNAs associated with neurogenesis, cell cycle, cell division, and DNA repair in PC12-derived nerve cells
Summary
Multiple myeloma (MM), which makes up around 10% of all haematological malignancies, is a malignant plasma cell disorder [1]. A major step forward in MM treatment has been the introduction of so-called novel agents, including the immunomodulatory drug (IMID) thalidomide, the subsequent development of its potent analogue lenalidomide, and the first-in-class proteasome inhibitor bortezomib (BZT) These agents serve a variety of anti-MM functions, including inhibition of MM cell proliferation and angiogenesis, apoptosis induction, and regulation of interactions between MM cells and bone marrow stromal cells [2]. The additional effect of bortezomib is based on the inhibition of DNA repair and angiogenesis, impairment of osteoclast activity [5] and disruption of intracellular calcium metabolism This can lead to mitochondrial calcium inflow and apoptosis induced by caspase activation [6]. Mitochondrial damage leads to oxidative stress through activation of ion channel TRPA1 in nociceptors
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