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Published on: October 20, 2016
Sulforaphane induces cell morphology change and cell apoptosis by activating endoplasmic reticulum stress in
Nan Li1, Yan Jiang2, Ajun Wang3
1Department of Neurosurgery, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China.
Background:
Sulforaphane (SFN), a naturally occurring isothiocyanate derived from cruciferous vegetables, has shown promise as a multitargeted therapeutic agent in glioblastoma (GBM). This study aimed to elucidate the role and underlying molecular mechanisms of SFN in regulating GBM progression, particularly through the endoplasmic reticulum stress (ERS) and unfolded protein response (UPR) pathways.
Methods:
Primary human glioma cells and established GBM cell lines were treated with various concentrations of SFN. RNA sequencing and qPCR analyses were conducted to identify transcriptional changes associated with the UPR pathway. Western blot and immunofluorescence were used to assess the expression and subcellular localization of key ER stress-related proteins. A CHOP knockdown model was employed to examine the functional role of CHOP in SFN-induced apoptosis. Additionally, normal human astrocytes (HA) were used to evaluate the selectivity of SFN's cytotoxicity. In vivo validation was performed using an intracranial glioma xenograft mouse model.
Results:
SFN significantly induced apoptotic cell death in GBM cells. Mechanistically, SFN activated multiple branches of the UPR, notably increasing the expression and nuclear translocation of ATF4 and CHOP. CHOP knockdown markedly attenuated SFN-induced apoptosis. RNA-seq and KEGG enrichment analyses confirmed the involvement of the ER stress pathway. Treatment with 4-phenylbutyrate (4-PBA) suppressed SFN-induced cytotoxicity, further supporting ER stress-mediated apoptosis. In vivo, SFN reduced tumor burden and upregulated ER stress markers in intracranial tumor tissues. Importantly, SFN had minimal cytotoxic effects on normal astrocytes, suggesting a favorable therapeutic window.
Conclusions:
This study demonstrates that SFN induces GBM cell apoptosis via activation of the UPR pathway, particularly through the ATF4-CHOP axis. These findings support the potential of SFN as a promising therapeutic agent for glioblastoma.
Insights
Sulforaphane (SFN) induces glioblastoma cell death by activating the unfolded protein response (UPR) pathway, specifically the ATF4-CHOP axis. This natural compound shows promise as a targeted glioblastoma therapy with minimal effects on normal cells.
Area of Science:
- Oncology
- Molecular Biology
- Neuroscience
Background:
- Glioblastoma (GBM) is an aggressive brain tumor with limited treatment options.
- Sulforaphane (SFN), a cruciferous vegetable compound, exhibits potential as a multitargeted therapeutic agent for GBM.
- Understanding SFN's molecular mechanisms, particularly its role in endoplasmic reticulum stress (ERS) and the unfolded protein response (UPR), is crucial for its therapeutic development.
Purpose of the Study:
- To investigate the role of SFN in glioblastoma progression.
- To elucidate the molecular mechanisms by which SFN affects GBM cells, focusing on ERS and UPR pathways.
- To evaluate the therapeutic potential and selectivity of SFN in preclinical models of glioblastoma.
Main Methods:
- SFN treatment of human glioma and GBM cell lines.
- RNA sequencing, qPCR, Western blot, and immunofluorescence to analyze UPR pathway activation and protein expression.
- CHOP knockdown and 4-phenylbutyrate (4-PBA) treatment to assess the role of specific UPR components and ER stress.
- In vivo studies using an intracranial glioma xenograft mouse model and assessment of SFN's cytotoxicity on normal human astrocytes.
Main Results:
- SFN significantly induced apoptosis in GBM cells.
- SFN activated UPR pathways, increasing ATF4 and CHOP expression and nuclear translocation, which were critical for SFN-induced apoptosis.
- SFN demonstrated reduced tumor burden in vivo and minimal toxicity to normal astrocytes, indicating a potential therapeutic window.
Conclusions:
- SFN induces glioblastoma cell apoptosis through the activation of the UPR pathway, mediated by the ATF4-CHOP axis.
- These findings highlight SFN as a promising therapeutic candidate for glioblastoma treatment.
- SFN's targeted action on GBM cells with minimal impact on normal astrocytes supports its potential clinical application.
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