Carfilzomib Suppresses SENP1 to Trigger Cardiotoxicity by DDX17 Destabilization
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA1144389 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR30132008.fastq.gz | Fastqsanger.gz | |||
| SRR30132009.fastq.gz | Fastqsanger.gz | |||
| SRR30132010.fastq.gz | Fastqsanger.gz | |||
| SRR30132011.fastq.gz | Fastqsanger.gz |
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Project description:Short interspersed element (SINE) RNAs are upregulated by cellular stresses1 (heat shock, DNA damage and viral infection) and accumulate in human diseases (macular degeneration2, lupus3, and Alzheimer’s disease4). These transcripts activate inflammasomes5, a family of cytoplasmic multiprotein complexes that sense danger molecules and initiate innate immune responses by activating caspase-1-dependent cytokine production and inflammatory death6, but the molecular sensor of SINE RNAs is unknown. Here, we identify DDX17, a member of the DEAD box family of RNA helicases7, as a sensor of SINE RNAs requisite for inflammasome activation. Induction of caspase-1 cleavage and release of IL-1 and IL-18 by SINE RNAs requires dual recruitment of NLRP3 and NLRC4 but proceeds independent of NAIPs, immune sensors required for canonical NLRC4 activation by bacterial proteins8,9. Instead, SINE RNAs trigger DDX17–NLRC4 interaction, which licenses inflammasome activation. We also report increased levels of DDX17 protein and association of DDX17 and NLRC4 in the retinal pigmented epithelium (RPE) of human eyes with an advanced, untreatable form of age-related macular degeneration (AMD). Disrupting DDX17–NLRC4 signalling blocks SINE RNA-induced inflammasome activation in human RPE cells and RPE degeneration in an animal model of AMD. Our findings uncover a non-canonical mode of inflammasome activation by endogenous retrotransposon transcripts, and provide new potential targets for macular degeneration and potentially other diseases.
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Project description:Whole Exome Sequencing Analysis of Carfilzomib-Related Cardiotoxicity in Multiple Myeloma Patients
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Project description:Hepatocellular carcinoma (HCC) ranks among one of the most prevalent and lethal cancers affecting humans. Currently, there are limited effective treatments available for HCC. In the search for potential anti-HCC agents, we found that carfilzomib, a proteasome inhibitor, exerts anti-HCC activities. However, the underlying mechanisms of action are main unclear. In this study, we evaluated the effectiveness of carfilzomib against HCC capability and explored its underlying mechanisms. Cell Counting Kit 8 (CCK8), EdU (5-ethynyl-2-deoxyuridine) staining, and colony formation assays were employed to analyze the antiproliferative ability of carfilzomib on MHCC-97H and Huh7 cells. Additionally, flow cytometry was used to assess the effect on the cell cycle. Western blotting was utilized to examine the protein expression levels associated with cell cycle arrest. Furthermore, short hairpin RNA (shRNA) transfection was used to investigate the role of GADD45a (growth arrest and DNA damage 45a) on carfilzomib-induced cell cycle arrest. A xenograft tumor model using nude mouse was employed to evaluate the anti-HCC activity of carfilzomib in vivo. The finding demonstrated that carfilzomib inhibited the proliferation, invasion, and migration in both MHCC-97H and Huh7 cells. In addition, carfilzomib caused cell cycle arrest by suppressing the expression of cyclin A1, cyclin E1, cyclin-dependent kinases 2 (CDK2), and cyclin-dependent kinases 4 (CDK4). It also upregulated the expression of GADD45a, and inhibition of GADD45a through shRNA abolished carfilzomib-induced cell cycle arrest in HCC cells. Importantly, carfilzomib demonstrated its ability to inhibit the Huh7 cell growth in vivo. Our research has revealed, for the first time, that carfilzomib inhibited the progression of HCC cells by upregulating GADD45a expression. These findings suggest that carfilzomib could be a potential chemotherapeutic agent against HCC.
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