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Next Generation Sequencing Facilitates Quantitative Analysis of transcriptomes in ARP-1 cells treated with DMSO and carfilzomib (Cfz)

ABSTRACT: The goals of NGS-derived retinal transcriptome profiling (RNA-seq) is to identify the signaling pathways in multiple myeloma (MM) cells affected by Cfz treatment. We treated ARP-1 MM cells with DMSO or 6nM Cfz for 16 hours (each group has 3 replicates) and extracted the total RNA using RNeasy Mini Kit (Qiagen). 5-10 µg RNA samples were sent to BGI genomics for RNA-seq followed by data analysis.

ORGANISM(S): Homo sapiens

PROVIDER: GSE143406 | GEO | 2020/05/07

REPOSITORIES: GEO

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Project description:Carfilzomib has a good effect in treating multiple myeloma, but more and more clinical studies have shown that the drug can cause cardiac toxicity during use, but the mechanism of action is unclear. This study aimed to comprehensively elucidate the mechanism of CFZ-induced cardiomyopathy by constructing a C57BL/6 mouse model and combining cell experiments. The research results showed that the hearts of mice treated with CFZ appeared significantly enlarged, and the cardiac function indicators decreased. The serum enzyme LDH, AST, and CK-MB levels significantly increased, suggesting severe myocardial injury. RNA extraction and QPCR detection of the heart showed that the expression of heart hypertrophy and fibrosis markers increased. Meanwhile, histological staining found that there were fewer cardiomyocytes, damaged myofibrils, and cardiac fibrosis. In the cell experiments, CFZ treatment caused the release of more LDH from rat cardiomyocytes and H9C2 cells, increased CASPASE 3/7 activity, abnormal cell morphology, enlarged cell size, myocardial hypertrophy and fibrosis marker gene expression in cardiomyocytes. Through the study of the SUMOYLATION pathway, it was found that CFZ's effects on cardiomyocyte structure and function were related to the expression of SENP genes, especially SENP1, which showed a significant downregulation in cardiomyocytes and mouse heart tissue, and was positively correlated with the levels of cardiac injury marker genes. This study further explored the mechanism of action by specifically altering the expression of SENP1 in cardiomyocytes. The results show that the knockdown of SENP1 in cardiomyocytes leads to more severe myocardial damage after CFZ treatment, suggesting that the expression of SENP1 can potentially affect the cardiotoxicity caused by CFZ. Further, by using silver staining and mass spectrometry to identify the interacting proteins with SENP1 after CFZ treatment, we found that the knockdown of DDX17 had a similar myocardial injury effect as SENP1. Subsequently, through Co-IP, protein stability experiments, and ubiquitination analysis experiments, we determined that SENP1 can maintain the protein stability of DDX17 by inhibiting its SUMO modification, thereby preventing cardiomyocyte injury and apoptosis. We hope to provide a new perspective and potential cardioprotective strategy for clinical use.

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Next Generation Sequencing Facilitates Quantitative Analysis of transcriptomes in ARP-1 cells treated with DMSO and carfilzomib (Cfz)

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