 |
 |
GEO help: Mouse over screen elements for information. |
|
| Status |
Public on Nov 04, 2022 |
| Title |
Effects of 17-DMAG treatment on transcription in 4T1 cells populations resistant and non-resistant to 17-DMAG |
| Organism |
Mus musculus |
| Experiment type |
Expression profiling by high throughput sequencing
|
| Summary |
Activation of endogenous retrotransposons frequently occurs in cancer cells and contributes to tumor genomic instability. To test whether inhibition of retrotranspositions has an anticancer effect, we used treatment with the nucleoside reverse transcriptase inhibitor (NRTI) stavudine in mouse cancer models, MMTV-HER2/Neu and Th-MYCN, that spontaneously develop breast cancer and neuroblastoma, respectively. In both cases, stavudine in drinking water did not affect tumor incidence nor demonstrate any direct antitumor effects. However, stavudine dramatically extended progression-free survival in both models following an initial complete response to chemotherapy. To approach the mechanism underlying this phenomenon, we analyzed the effect of NRTI on the selection of treatment-resistant variants in tumor cells in culture. Cultivation of mouse breast carcinoma 4T1 in the presence of stavudine dramatically reduced the frequency of cells capable of surviving treatment with anticancer drugs. Global transcriptome analysis demonstrated that the acquisition of drug resistance by 4T1 cells was accompanied by an increase in the constitutive activity of interferon type I and NF-ϰB pathways and an elevated expression of LINE-1 elements, which are known to induce inflammatory responses via their products of reverse transcription. Treatment with NRTI reduced NF-ϰB activity and reverted drug resistance. Furthermore, the inducible expression of LINE-1 stimulated inflammatory response and increased the frequency of drug resistant variants in a tumor cell population. These results indicate a new mechanism by which retrotransposon desilencing can stimulate tumor cell survival during treatment and suggest reverse transcriptase inhibition as a potential new therapeutic approach for targeting the development of drug resistant cancers.
|
| |
|
| Overall design |
RNA isolation was performed from subconfluent cultures. Independently generated cell populations resistant to treatment with HSP90 inhibitor 17-DMAG (4T1R1 and 4T1R2) were obtained by several cycles of exposure of the initial population of 4T1 cells to 1 ug/ml of 17-DMAG for 24 hours following the expansion of surviving cells in 17-DMAG-free medium. RNA was isolated from untreated cells ("untreated") and 2 hours following 17-DMAG treatment ("DMAG-treated") in three biological replicas ("Rep 1-3").
|
| |
|
| Contributor(s) |
Gudkov A, Novototskaya-Vlasova K, Neznanov N, Molodtsov I |
| Citation(s) |
36449545 |
| |
| Submission date |
Nov 01, 2022 |
| Last update date |
Feb 10, 2023 |
| Contact name |
Andrei Gudkov |
| E-mail(s) |
andrei.gudkov@roswellpark.org
|
| Organization name |
Roswell Park Comprehensive Cancer Center
|
| Department |
Department of Cell Stress Biology
|
| Street address |
Elm and Carlton Streets
|
| City |
Buffalo |
| State/province |
NY |
| ZIP/Postal code |
14263 |
| Country |
USA |
| |
|
| Platforms (1) |
| GPL24247 |
Illumina NovaSeq 6000 (Mus musculus) |
|
| Samples (18)
|
| GSM6704007 |
4T1R1 cells, DMAG-treated, rep1 |
| GSM6704008 |
4T1R1 cells, DMAG-treated, rep2 |
| GSM6704009 |
4T1R1 cells, DMAG-treated, rep3 |
| GSM6704010 |
4T1 cells, untreated, rep1 |
| GSM6704011 |
4T1 cells, untreated, rep2 |
| GSM6704012 |
4T1 cells, untreated, rep3 |
| GSM6704013 |
4T1R2 cells, untreated, rep1 |
| GSM6704014 |
4T1R2 cells, untreated, rep2 |
| GSM6704015 |
4T1R2 cells, untreated, rep3 |
| GSM6704016 |
4T1 cells, DMAG-treated, rep1 |
| GSM6704017 |
4T1 cells, DMAG-treated, rep2 |
| GSM6704018 |
4T1 cells, DMAG-treated, rep3 |
| GSM6704019 |
4T1R2 cells, DMAG-treated, rep1 |
| GSM6704020 |
4T1R2 cells, DMAG-treated, rep2 |
| GSM6704021 |
4T1R2 cells, DMAG-treated, rep3 |
|
| This SubSeries is part of SuperSeries: |
| GSE217043 |
Inflammatory response to retrotransposons drives tumor drug resistance that can be prevented by reverse transcriptase inhibitors |
|
| Relations |
| BioProject |
PRJNA896604 |
| Supplementary file |
Size |
Download |
File type/resource |
| GSE217036_processed_data.txt.gz |
615.2 Kb |
(ftp)(http) |
TXT |
SRA Run Selector |
| Raw data are available in SRA |
| Processed data are available on Series record |
|
|
|
|
 |
Less...
More...