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Effect of Bortezomib on Global Gene Expression in PC12-Derived Nerve Cells
Karolina Łuczkowska1, Dorota Rogińska1, Zofia Ulańczyk1
1Department of General Pathology, Pomeranian Medical University, 70-111 zip code Szczecin, Poland.
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.
Insights
Bortezomib treatment significantly alters gene and microRNA expression in nerve cells, affecting crucial cellular processes. This study identifies specific gene and microRNA changes linked to bortezomib-induced neurotoxicity.
Area of Science:
- Neuroscience
- Molecular Biology
- Oncology
Background:
- Peripheral neuropathy is a common side effect of oncohematological therapeutics.
- The precise molecular mechanisms of drug-induced neurotoxicity remain unclear.
- Bortezomib is a therapeutic agent used in oncohematological diseases.
Purpose of the Study:
- To investigate the impact of bortezomib on global gene and microRNA expression.
- To elucidate molecular mechanisms of bortezomib-induced neurotoxicity in nerve cells.
Main Methods:
- Microarray analysis was performed on PC12-derived nerve cells treated with bortezomib.
- Global gene expression profiling was conducted.
- MicroRNA expression analysis was performed, followed by correlation analysis with mRNA data.
Main Results:
- Bortezomib treatment resulted in significant downregulation (1383 genes) and upregulation (671 genes) of gene expression.
- Downregulated processes included cell cycle regulation, DNA replication/repair, cell migration, neuron morphogenesis, and neurotransmitter secretion.
- Eleven microRNAs were significantly downregulated, with notable correlations between decreased miR-130a-3p/miR-152-3p and increased Gadd45 expression.
Conclusions:
- Bortezomib profoundly affects gene and microRNA expression in nerve cells.
- Altered expression of specific genes and microRNAs, like Gadd45, may contribute to bortezomib-induced neurotoxicity.
- Further research into these molecular pathways can inform strategies to mitigate neurotoxic side effects.
