-
Categories
-
Pharmaceutical Intermediates
-
Active Pharmaceutical Ingredients
-
Food Additives
- Industrial Coatings
- Agrochemicals
- Dyes and Pigments
- Surfactant
- Flavors and Fragrances
- Chemical Reagents
- Catalyst and Auxiliary
- Natural Products
- Inorganic Chemistry
-
Organic Chemistry
-
Biochemical Engineering
- Analytical Chemistry
-
Cosmetic Ingredient
- Water Treatment Chemical
-
Pharmaceutical Intermediates
Promotion
ECHEMI Mall
Wholesale
Weekly Price
Exhibition
News
-
Trade Service
Recently, Adam Kosti et al.
of Texas State University in the United States used high-throughput sequencing screening, western blotting, transcriptomics analysis, lipidomics analysis and survival analysis to discover the key molecule that simultaneously regulates the receptor tyrosine kinase signaling pathway and lipid dynamics, namely E74-like ETS transcription factor 4
.
The effects of the molecule and its two pathways on the GBM phenotype, its mechanism of action and its importance for GBM treatment were verified
by in vivo and in vitro experiments.
The results were published online
in the July 2022 issue of Neuro-Oncology.
—Excerpted from the article chapter
【Ref: Kosti A, et al.
Neuro Oncol.
2022 Jul 21; noac179.
doi: 10.
1093/neuonc/noac179.
[Epub ahead of print] 】
Research background
Glioblastoma multiforme (GBM) is the most common and aggressive brain tumor in adults, with a median survival time of only 13 months
.
A series of sequencing efforts are currently being carried out for GBM, but targeted therapies for different subtypes have not yet been achieved
.
GBM exhibits significant transcriptome plasticity, which can achieve molecular subtype conversion under the action of treatment and other factors, thereby resisting treatment and tumor recurrence
.
Understanding gene regulation, identifying synergistic antagonistic interactions between genes, and the impact of genes on GBM phenotypes and related pathways are critical
to improving treatment outcomes and preventing recurrence.
Recently, Adam Kosti et al.
of Texas State University in the United States used high-throughput sequencing screening, western blotting, transcriptomics analysis, lipidomics analysis and survival analysis to discover the key molecule that simultaneously regulates the receptor tyrosine kinase (RTK) signaling pathway and lipid dynamics, namely E74-like ETS transcription factor 4 (ELF4).
The effects of the molecule and its two pathways on the GBM phenotype, its mechanism of action and its importance for GBM treatment were verified
by in vivo and in vitro experiments.
The results were published online
in the July 2022 issue of Neuro-Oncology.
Research results
The results show that the key gene
ELF4 in the transcription factor network was identified by high-throughput screening of GBM cell lines and the effects of cell proliferation, apoptosis and expression on patient survival.
Combined with TCGA and CGGA database verification, it was found that the expression of ELF4 was higher
in GBM/relapse group/ and more aggressive GBM subgroup than in normal tissue and low-grade glioma/primary group/less invasive GBM subgroup.
Knockdown of ELF4 in glioma stem cell lines (GSCs) found significant inhibition
of cell proliferation.
In the in situ model of mouse glioma, the survival rate of mice in the ELF4 knockout group was significantly increased, and after doxycycline treatment, the intracranial tumor volume of the mice in the knockout group was significantly smaller
than that in the control group.
After enriching ELF4-related functions using transcriptome analysis, the researchers found that the gene was related to the regulation of neuronal differentiation, extracellular matrix organization, receptor signaling and lipid transport.
ELF4 has a particularly significant
effect on receptor tyrosine kinase (RTK) signaling and lipid homeostasis.
The luciferase reporter experiment was used to reveal that ELF4 directly modulates the RTK-MAPK signaling pathway
.
Through lipidomic analysis, the authors believe that ELF4 is important for maintaining specific phospholipid levels; After knocking down ELF4, phosphocholine (PC) and phosphatidylethanolamine (PE) levels were significantly reduced, and the correlation
between ELF4 and lipid balance was further confirmed by protein interaction.
RTK signaling and lipid balance are two codependent and mutually reinforcing pathways, one gene increases the phospholipid pool, and the other is directly responsible for RTK signaling
.
As a forward regulator of interconnected genes, ELF4 participates in both pathways and acts as
a bridge factor between the two pathways.
Based on the mechanism of action of ELF4 in GBM found above, the authors targeted GSCs by combining RTK inhibitors (dasatinib) and lipid balance inhibitors (lovastatin); It was found that the two drugs had a synergistic effect and could effectively reduce the cell viability of GSCs and inhibit their proliferation, and the mechanism was similar
to that of reducing their expression after knocking down ELF4.
Conclusion of the study
In summary, the study shows that ELF4 is a transcription factor involved in the regulation of RTK signaling and lipid dynamics pathways at the same time, reducing ELF4 expression levels can inhibit tumor proliferation and growth, and combining drugs that inhibit these two pathways at the same time may have a synergistic effect, similar to knocking down or knocking out ELF4, which may have potential therapeutic effects in GBM patients, and the study provides new ideas and approaches
for the treatment of GBM.
