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| Status |
Public on May 05, 2021 |
| Title |
EGFR/FOXO3a/BIM signalling pathway determines chemosensitivity of BMP4-differentiated glioma stem cells to temozolomide |
| Organism |
Homo sapiens |
| Experiment type |
Expression profiling by high throughput sequencing
|
| Summary |
Accumulating evidence suggests that glioma stem cells (GSCs), rare cells characterised by pluripotency and self-renewal, are responsible for glioblastoma (GBM) propagation, recurrence and resistance to therapy. Differentiation with bone morphogenic proteins (BMPs) is considered to be a promising approach to eliminate GSCs and sensitise glioma to chemotherapeutics. Epidermal growth factor receptor (EGFR) gene alterations are detected in more than a half of GBMs, however, the role of EGFR in chemoresistance of glioma stem cells remain elusive. Here, we investigated whether EGFR signalling affects BMP4-induced differentiation of GSCs and their response to an alkylating drug temozolomide (TMZ). We show that BMP4 triggers Smad signalling cascade in glioma stem cells independently of the EGFR level. BMP4 down-regulated levels of pluripotency markers (SOX2 and OLIG2) with the concomitant induction of astrocytic (GFAP) and neuronal (b-Tubulin III) markers. However, significant differences in chemotherapy outcomes were observed in glioma stem cells with different EGFR levels. BMP4-induced differentiation did not enhance sensitivity to TMZ in EGFRlow GSCs, in contrast to EGFRhigh GSCs, which were undergoing apoptosis. We identified differences in cell cycle regulation by analyses of cell cycle phase distribution and cell-cycle-related proteins. In cells with lower EGFR expression BMP4 triggered the G1 cell cycle arrest, not detected in EGFRhigh cells. RNA-seq profiles further highlighted transcriptomic alternations and distinct processes characterizing EGFR-dependent responses in course of BMP4-induced differentiation. We identified AKT/FOXO3a axis controlling of BIM (the pro-apoptotic BCL-2 family protein) as operating only in EGFRhigh BMP4-differentiated and TMZ-treated cells.
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| Overall design |
Examination of BMP4-triggered differentiation of glioma stem cells with regard to EGFR signaling
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| Contributor(s) |
Ciechomska IA, Gielniewski B, Wojtas B, Kaminska B, Mieczkowski J |
| Citation(s) |
32788653 |
| |
| Submission date |
Nov 15, 2019 |
| Last update date |
May 05, 2021 |
| Contact name |
Jakub Mieczkowski |
| E-mail(s) |
jmieczkowski@jmieczkowski.pl
|
| Organization name |
Medical University of Gdansk
|
| Street address |
Debinki 12
|
| City |
Gdansk |
| ZIP/Postal code |
80-211 |
| Country |
Poland |
| |
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| Platforms (1) |
| GPL18460 |
Illumina HiSeq 1500 (Homo sapiens) |
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| Samples (12)
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| Relations |
| BioProject |
PRJNA589752 |
| SRA |
SRP230182 |
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