 |
 |
GEO help: Mouse over screen elements for information. |
|
| Status |
Public on May 23, 2024 |
| Title |
Anti-tumor effects of the eIF4A Inhibitor didesmethylrocaglamide and its derivatives in human and canine osteosarcomas |
| Organism |
Homo sapiens |
| Experiment type |
Expression profiling by high throughput sequencing
|
| Summary |
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.
|
| |
|
| Overall design |
RNA sequencing of MG-63 and Saos2 human osteosarcoma cells treated for 24 hours with DMSO or 1x growth-inhibitory IC50 of the eIF4A1/2 inhibitors rocaglamide (Roc) or didesmethylrocaglamide. MG-63 treatment was conducted as two biological replicates and Saos2 cells as three biological replicates.
|
| |
|
| Contributor(s) |
Chang L, Oblinger J |
| Citation(s) |
38947012, 39164287 |
| |
| Submission date |
May 18, 2024 |
| Last update date |
Sep 27, 2024 |
| Contact name |
Long-Sheng Chang |
| E-mail(s) |
Long-Sheng.Chang@nationwidechildrens.org
|
| Phone |
6143552658
|
| Organization name |
Research Institute at Nationwide Children's Hospital
|
| Department |
Center for Childhood Cancer
|
| Lab |
Chang Lab
|
| Street address |
575 Children's Crossroad, WC-5574, Ctr for Childhood Cancer & Dept of Pediatrics, Nationwide Children's Hosp & The Ohio State U
|
| City |
Columbus |
| State/province |
Ohio |
| ZIP/Postal code |
43215 |
| Country |
USA |
| |
|
| Platforms (1) |
| GPL24676 |
Illumina NovaSeq 6000 (Homo sapiens) |
|
| Samples (15)
|
| GSM8279160 |
MG-63, 5 nM DDR, biol replicate 2 |
| GSM8279161 |
MG-63, 25 nM Roc, biol replicate 1 |
| GSM8279162 |
MG-63, 25 nM Roc, replicate 2 |
| GSM8279163 |
Saos2, DMSO, biol replicate 1 |
| GSM8279164 |
Saos2, DMSO, biol replicate 2 |
| GSM8279165 |
Saos2, DMSO, biol replicate 3 |
| GSM8279166 |
Saos2, 7 nM DDR, biol replicate 1 |
| GSM8279167 |
Saos2, 7 nM DDR, biol replicate 2 |
| GSM8279168 |
Saos2, 7 nM DDR, biol replicate 3 |
| GSM8279169 |
Saos2, 40 nM Roc, biol replicate 1 |
| GSM8279170 |
Saos2, 40 nM Roc, biol replicate 2 |
| GSM8279171 |
Saos2, 40 nM Roc, biol replicate 3 |
|
| Relations |
| BioProject |
PRJNA1113160 |
| Supplementary file |
Size |
Download |
File type/resource |
| GSE267810_MG63DEG_DMSOvDDR_DESeq2shrinkage.xlsx |
10.6 Mb |
(ftp)(http) |
XLSX |
| GSE267810_MG63DEG_DMSOvRoc_DESeq2shrinkage.xlsx |
10.4 Mb |
(ftp)(http) |
XLSX |
| GSE267810_MG63_RawAndNormalizedCounts.xlsx |
6.8 Mb |
(ftp)(http) |
XLSX |
| GSE267810_Saos2DEG_DMSOvDDR_DESeq2shrinkage.xlsx |
9.9 Mb |
(ftp)(http) |
XLSX |
| GSE267810_Saos2DEG_DMSOvRoc_DESeq2shrinkage.xlsx |
9.9 Mb |
(ftp)(http) |
XLSX |
| GSE267810_Saos2_RawAndNormalizedCounts.xlsx |
10.0 Mb |
(ftp)(http) |
XLSX |
SRA Run Selector |
| Raw data are available in SRA |
|
|
|
|
 |
Less...
More...