Ivermectin inhibits the growth of esophageal squamous cell carcinoma by activating ATF4-mediated endoplasmic reticulum stress-autophagy pathway
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ABSTRACT:
PROVIDER: PRJNA831453 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR18907490_1.fastq.gz | Fastqsanger.gz | |||
| SRR18907490_2.fastq.gz | Fastqsanger.gz | |||
| SRR18907491_1.fastq.gz | Fastqsanger.gz | |||
| SRR18907491_2.fastq.gz | Fastqsanger.gz | |||
| SRR18907492_1.fastq.gz | Fastqsanger.gz |
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Project description:Esophageal squamous cell carcinoma (ESCC) is one of the most common form of malignancies in the world. However, there is currently a lack of effective chemotherapeutic drugs for ESCC, and it is urgent to develop new and safe drugs for this disease. Ivermectin is a broad-spectrum antiparasitic drug with demonstrable antitumor activity. However, the precise cellular and molecular mechanisms of ivermectin in cancers growth inhibition remain unclear. In this study, we report a role of ivermectin in ESCC suppression by activating the endoplasmic reticulum (ER) stress and autophagy. In transcriptome analysis, we found that ATF4 and DDIT3 are involved in ER stress activation by ivermectin. Moreover, ivermectin treatment suppressed the growth of ESCC xenograft tumors in nude mice. Taken together, our results identify the antitumor molecular basis of ivermectin targeting the ER stress-autophagy pathway and suggest that ivermectin is a potential drug for the treatment of ESCC.
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Project description:Pancreatic beta-cell dysfunction and eventual beta-cell loss are key steps in the course of type 2 diabetes (T2D). Endoplasmic reticulum (ER) stress, in particular the PERK-ATF4 pathway, has been implicated in promoting these beta-cell pathologies. However, the exact molecular events surrounding the PERK-ATF4 pathway in beta-cell dysfunction remain unknown. Here, we discovered that ATF4 transcriptionally promotes expression of PDE4D, which results in beta-cell dysfunction via downregulation of cAMP signaling. Beta-cell-specific transgenic expression of ATF4 resulted in early beta-cell dysfunction and loss, resembling accelerated T2D. ATF4 expression, rather than CHOP, promoted PDE4D expression, decreased cAMP signaling, and attenuated responses to incretins and elevated glucose. Further, beta-cells of leptin receptor-deficient diabetic (db/db) mice expressed increased levels of ATF4 and PDE4D, accompanying impaired beta-cell function. Moreover, inhibiting PDE4D activity with selective pharmacological inhibitors significantly ameliorated beta-cell dysfunction in both db/db mice and beta-cell-specific ATF4 transgenic mice. In summary, our findings support that ER stress causes beta-cell failure via ATF4-mediated PDE4D production, and this is a highly promising therapeutic target for protecting beta-cell function during progression of T2D.
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Project description:In eukaryotic cells, the spatial regulation of protein expression is frequently conferred through the coupling of mRNA localization and the local control of translation. mRNA localization to the endoplasmic reticulum (ER) is a prominent example of such regulation and serves a ubiquitous role in segregating the synthesis of secretory and integral membrane proteins to the ER. Recent genomic and biochemical studies have now expanded this view to suggest a role for the ER in global protein synthesis. We have utilized cell fractionation and ribosome profiling to obtain a genomic survey of the subcellular organization of mRNA translation and report that ribosomal loading of mRNAs, a proxy for mRNA translation, is biased to the ER. Notably, ER-associated mRNAs encoding both cytosolic and topogenic signal-encoding proteins display similar ribosome loading densities, suggesting that ER-associated ribosomes serve a global role in mRNA translation. We propose that the partitioning of mRNAs and their translation between the cytosol and ER compartments may represent a novel mechanism for the post-transcriptional regulation of gene expression. HEK293 cells were fractionated between the cytosol and endoplasmic reticulum. Within each fraction, ribosome footprints were generated and sequenced. In parallel, total mRNA was sequenced.
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Project description:Disruptions of the endoplasmic reticulum (ER) that perturb protein folding cause ER stress and elicit an unfolded protein response (UPR) that involves translational and transcriptional changes in gene expression aimed at expanding the ER processing capacity and alleviating cellular injury. Three ER stress sensors PERK, ATF6, and IRE1 implement the UPR. PERK phosphorylation of eIF2 during ER stress represses protein synthesis, which prevents further influx of ER client proteins, along with preferential translation of ATF4, a transcription activator of the integrated stress response. In this study we show that the PERK/eIF2α~P/ATF4 pathway is required not only for translational control, but also activation of ATF6 and its target genes. The PERK pathway facilitates both the synthesis of ATF6 and trafficking of ATF6 from the ER to the Golgi for intramembrane proteolysis and activation of ATF6. As a consequence, liver-specific depletion of PERK significantly reduces both the translational and transcriptional phases of the UPR, leading to reduced protein chaperone expression, disruptions of lipid metabolism, and enhanced apoptosis. These findings show that the regulatory networks of the UPR are fully integrated, and helps explain the diverse pathologies associated with loss of PERK. 14 gene expression arrays, 3 WT control arrays; 3 lsPERK control arrays; 4 WT Treated arrays; 4 lsPERK treated arrays. Comparison of gene expression profiles for treated vs control in wildtype and knock-out.
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