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Anti-tumor effects of the eIF4A Inhibitor didesmethylrocaglamide and its derivatives in human and canine osteosarcomas

ABSTRACT: Anti-tumor effects of the eIF4A Inhibitor didesmethylrocaglamide and its derivatives in human and canine osteosarcomas

PROVIDER: PRJNA1113160 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR29076614_1.fastq.gz	Fastqsanger.gz
	SRR29076614_2.fastq.gz	Fastqsanger.gz
	SRR29076615_1.fastq.gz	Fastqsanger.gz
	SRR29076615_2.fastq.gz	Fastqsanger.gz
	SRR29076616_1.fastq.gz	Fastqsanger.gz

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Anti-tumor effects of the eIF4A Inhibitor didesmethylrocaglamide and its derivatives in human and canine osteosarcomas

Project description:Inhibition of translation initiation using eIF4A inhibitors like (-)-didesmethylrocaglamide [(-)-DDR] and (-)-rocaglamide [(-)-Roc] is a potential cancer treatment strategy as they simultaneously diminish multiple oncogenic drivers. We showed that human and dog osteosarcoma cells expressed high levels of eIF4A1/2, which are important for cell growth. To advance preclinical development of eIF4A inhibitors, the importance of (-)-chirality in DDR for growth-inhibitory activity was demonstrated. Bromination of DDR at carbon-5 abolished growth-inhibitory activity, while acetylating DDR at carbon-1 was tolerated. Like DDR and Roc, DDR-acetate increased the γH2A.X levels and induced G2/M arrest and apoptosis. These rocaglates decreased the levels of several mitogenic kinases, the STAT3 transcription factor, and the stress-activated protein kinase p38. However, phosphorylated p38 was greatly enhanced, implying activation of stress response pathways. Importantly, these rocaglates potently suppressed canine osteosarcoma patient-derived xenografts. These results suggest that these eIF4A inhibitors can be leveraged to treat both human and dog osteosarcomas.

2024-05-23 | GSE267810 | GEO

Canine osteosarcoma cell lines and tissues

Project description:Cell lines and tumor tissues from canine osteosarcomas with accompanying survival and breed data.

2011-09-08 | GSE27217 | GEO

Anti-tumor effects of the eIF4A inhibitor didesmethylrocaglamide and its derivatives in human and canine osteosarcomas.

Project description:Inhibition of translation initiation using eIF4A inhibitors like (-)-didesmethylrocaglamide [(-)-DDR] and (-)-rocaglamide [(-)-Roc] is a potential cancer treatment strategy as they simultaneously diminish multiple oncogenic drivers. We showed that human and dog osteosarcoma cells expressed higher levels of eIF4A1/2 compared with mesenchymal stem cells. Genetic depletion of eIF4A1 and/or 2 slowed osteosarcoma cell growth. To advance preclinical development of eIF4A inhibitors, we demonstrated the importance of (-)-chirality in DDR for growth-inhibitory activity. Bromination of DDR at carbon-5 abolished growth-inhibitory activity, while acetylating DDR at carbon-1 was tolerated. Like (-)-DDR, (±)-DDR, and (-)-Roc, (±)-DDR-acetate increased γH2A.X levels and induced G2/M arrest and apoptosis. Consistent with translation inhibition, these rocaglates decreased the levels of several mitogenic kinases, the STAT3 transcription factor, and the stress-activated protein kinase p38. However, phosphorylated p38 was greatly enhanced in treated cells, suggesting activation of stress response pathways. RNA sequencing identified RHOB as a top upregulated gene in both (-)-DDR- and (-)-Roc-treated osteosarcoma cells, but the Rho inhibitor Rhosin did not enhance the growth-inhibitory activity of (-)-DDR or (-)-Roc. Nonetheless, these rocaglates potently suppressed tumor growth in a canine osteosarcoma patient-derived xenograft model. These results suggest that these eIF4A inhibitors can be leveraged to treat both human and dog osteosarcomas.

| S-EPMC11335891 | biostudies-literature

Ribosome profiling upon inhibition of eIF4A

Project description:Ribosome profiling of MDA-MB-231 cells treated with Silvestrol to monitor transcriptome wide, eIF4A-dependent changes in translation efficiency Translation efficiency (TE) of mRNAs dervied from ribosome footprints was monitored in the presence or absence of 25 nM Silvestrol, an inhibitor of eukaryotic translation initiation factor 4A (eIF4A). Transcripts with reduced TE in the presence of Silvestrol were compare to transcripts with reduced TE in the presence of INK128, a catalytic mTOR inhbitor.

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Canine osteosarcoma cell lines and tissues

Project description:Cell lines and tumor tissues from canine osteosarcomas with accompanying survival and breed data. Comparisons of gene expression between osteosarcoma-derived cell lines and osteosarcoma tissues.

2011-09-07 | E-GEOD-27217 | biostudies-arrayexpress

Dual targeting of DDX3 and eIF4A by the translation inhibitor rocaglamide A

Project description:Small molecule compounds that sense the nucleic acid sequences, promise the attractive venue for drug development. Such an unusual effect has been observed in the natural product Rocaglamide A (RocA) from Aglaia plant, proving to exhibit anti-tumor effects by clamping eukaryotic initiation factor (eIF) 4A onto mRNA polypurine sequences. Although eIF4A has been speculated the unique target of RocA, the insensitization of eIF4A in human cells only partially rescued the translation repression from RocA, suggesting another alternative target of this compound. Here, we revealed that DDX3 is an alternative target of RocA. Developing a RocA derivative with an O-nitrobenzoxadiazole unit (RocA-O-NBD), which can covalently bind to proximate proteins and provide fluorescence to them, we identified DDX3 bound to RocA. As observed in eIF4A, RocA locked the DDX3 protein onto polypurine sequences of RNA in an ATP-independent manner. De novo assembled Aglaia plant transcriptome uncovered the natural amino acid substitutions in Aglaia DDX3 to protect itself from RocA toxicity. Because of the dominant negative effect of RocA, we also proved the protein abundance of eIF4A and DDX3 in cancer cells determines their sensitivity to RocA. Overall, this study discovered DDX3 as another target of RocA and suggests the probability to predict tumor toxicity of RocA by the target abundance.

2020-12-07 | GSE148636 | GEO

Mapping the Interaction between Eukaryotic Initiation Factor 4A (eIF4A) and the Inhibitor Hippuristanol Using Carbene Footprinting and Mass Spectrometry

Project description:Protein-ligand interactions are central to protein activity and cell functionality. Improved knowledge of these relationships greatly benefits our understanding of key biological processes and aids in rational drug design towards the treatment of clinically relevant diseases. Carbene footprinting is a recently developed mass spectrometry-based chemical labelling technique that provides valuable information relating to protein-ligand interactions, such as the mapping of binding sites and associated conformational change. Here we show the application of carbene footprinting to the interaction between eIF4A helicase and a natural product inhibitor, hippuristanol, found in the coral Isis hippuris. Upon addition of hippuristanol we identified reduced carbene labelling (masking) in regions of eIF4A previously implicated in ligand binding. Additionally, we detected hippuristanol-associated increased carbene labelling (unmasking) around the flexible hinge region of eIF4A, indicating ligand-induced conformational change. This work represents further development of the carbene footprinting technique and demonstrates its potential in characterising medicinally relevant protein-ligand interactions.

2021-08-25 | PXD025105 | Pride

Dual targeting of DDX3 and eIF4A by the translation inhibitor rocaglamide A

Project description:Dual targeting of DDX3 and eIF4A by the translation inhibitor rocaglamide A

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Rocaglates convert DEAD-box protein eIF4A into a sequence-selective translational repressor

Project description:Rocaglamide A (RocA) typifies a class of protein synthesis inhibitors that selectively kill aneuploid tumor cells and repress translation of specific mRNAs. RocA targets eukaryotic initiation factor 4A (eIF4A), an ATP-dependent DEAD-box RNA helicase; its mRNA selectivity is proposed to reflect highly structured 5â² UTRs that depend strongly on eIF4A-mediated unwinding. However, rocaglate treatment may not phenocopy the loss of eIF4A activity, as these drugs actually increase the affinity between eIF4A and RNA. Here, we show that secondary structure in 5â² UTRs is only a minor determinant for RocA selectivity and RocA does not repress translation by reducing eIF4A availability. Rather, in vitro and in cells, RocA specifically clamps eIF4A onto polypurine sequences in an ATP-independent manner. This artificially clamped eIF4A blocks 43S scanning, leading to premature, upstream translation initiation and reducing protein expression from transcripts bearing the RocA-eIF4A target sequence. In elucidating the mechanism of selective translation repression by this lead anti-cancer compound, we provide an example of a drug stabilizing sequence-selective RNA-protein interactions. Bind-n-Seq and iCLIP-Seq

2016-06-15 | E-GEOD-79392 | biostudies-arrayexpress

Transcriptomic analysis of two human pancreatic cancer cell lines treated with the HDAC inhibitor romidepsin and/or the RNA helicase eIF4A inhibitor des-methyl pateamine A

Project description:Our study explores a small molecule combination that induces epigenetic reprogramming as a novel therapeutic strategy for pancreatic cancer. We have identified marked sensitivity of pancreatic cancer cells to the combination of a novel inhibitor of RNA helicase eIF4A, des-methyl pateamine A (DMPatA or MZ735), and a histone deacetylase (HDAC) inhibitor, romidepsin. A short-duration, low dose exposure to romidepsin treatment, when combined with DMPatA, triggers persistent global histone acetylation, transcriptional upregulation, replication inhibition, and augmented DNA damage. This combined effect induces a synergistic anti-proliferative response in pancreatic cancer cell lines.

2025-07-01 | GSE271450 | GEO

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