Taxifolin promotes glioma stem cell differentiation via CYP1B1-mediated EMT suppression
Mengxin Li1, Jiaying Yang2, Keyan Wang3
1Department of Plastic Surgery, China-Japan Union Hospital of Jilin University, Changchun, China; Department of breast surgery, The First Hospital of Jilin University, Changchun, China.
Background:
Glioblastoma (GBM) progresses aggressively and resists therapy largely due to glioma stem cells (GSCs), which drive recurrence and treatment failure. Inducing GSC differentiation into non-stem-like cells offers a promising therapeutic approach. Taxifolin (TAX), a natural flavonoid with anti-inflammatory and antioxidant properties, has demonstrated anti-stemness effects in cancer but its impact on GSCs remains unclear.
Purpose:
The study aimed to explore TAX as a differentiation-inducing agent targeting GSCs to enhance therapeutic response in GBM.
Study Design:
We assessed the effects and mechanism of TAX on GSC proliferation, self-renewal, and differentiation using in vitro and in vivo models, supported by transcriptomic and rescue experiments.
Methods:
Using human (TS576) and murine (CSC2078) GSC lines, along with an orthotopic xenograft model, we examined the effects of TAX on proliferation, self-renewal, and differentiation, as well as its downstream pathway. Funcional assays including cell viability, colony formation, neurosphere formation, apoptosis, and differentiation marker analysis were conducted in vitro. Transcriptomic profiling and KEGG pathway enrichment identified CYP1B1 as a key downstream target, whose role was validated through overexpression-based rescue experiments and epithelial-mesenchymal transition (EMT) marker analysis. TAX efficacy and biosafety were evaluated using bioluminescence imaging, histopathology and immunohistochemistry in vivo, with temozolomide as a positive control.
Results:
Purified TAX (92.47%) from Larix olgensis roots inhibited the proliferation, self-renewal of GSCs and induced apoptosis. TAX promoted GSCs differentiation toward neuronal lineages, supporting its potential as a differentiation-based adjuvant therapy. TAX suppressed tumor growth without observable toxicity and enhanced the therapeutic efficacy of temozolomide (TMZ) in vivo. Bioinformatic analysis identified CYP1B1 as a TAX-responsive target, with elevated expression in glioma tissues and strong association with malignancy and poor prognosis. Functional assays confirmed that CYP1B1 overexpression promotes EMT, while TAX downregulates CYP1B1 and inhibits EMT progression.
Conclusion:
This study is the first to demonstrate that TAX promotes neuronal differentiation of GSCs by suppressing the CYP1B1-mediated EMT pathway. Our work uncovers a novel mechanism linking CYP1B1 down-regulation to GSC differentiation. These findings establish TAX as a differentiation-inducing agent and propose a new therapeutic strategy for GBM by targeting stemness and EMT concurrently.
Insights
Taxifolin (TAX) promotes neuronal differentiation in glioblastoma stem cells (GSCs) by inhibiting the CYP1B1-mediated epithelial-mesenchymal transition (EMT) pathway. This study establishes TAX as a novel therapeutic agent for glioblastoma (GBM).
Area of Science:
- Oncology
- Stem Cell Biology
- Pharmacology
Background:
- Glioblastoma (GBM) is an aggressive brain cancer driven by glioma stem cells (GSCs), which contribute to treatment resistance and recurrence.
- Inducing GSC differentiation is a potential therapeutic strategy to overcome GBM's therapeutic challenges.
- Taxifolin (TAX), a natural flavonoid, has shown anti-stemness properties, but its specific effects on GSCs require elucidation.
Purpose of the Study:
- To investigate Taxifolin's (TAX) potential as a differentiation-inducing agent for glioma stem cells (GSCs).
- To explore TAX's mechanism of action in targeting GSCs and enhancing glioblastoma (GBM) therapeutic responses.
- To evaluate TAX's efficacy and safety in preclinical GBM models.
Main Methods:
- Assessed TAX effects on GSC proliferation, self-renewal, and differentiation using human and murine GSC lines in vitro and an orthotopic xenograft model in vivo.
- Conducted functional assays, transcriptomic profiling, and KEGG pathway enrichment to identify downstream targets and mechanisms.
- Validated the role of CYP1B1 as a key target and assessed its association with epithelial-mesenchymal transition (EMT) and GBM malignancy.
- Evaluated in vivo efficacy and biosafety using bioluminescence imaging and histopathology, with temozolomide (TMZ) as a positive control.
Main Results:
- Purified TAX inhibited GSC proliferation and self-renewal, induced apoptosis, and promoted neuronal differentiation.
- TAX suppressed tumor growth in vivo without observable toxicity and enhanced temozolomide (TMZ) efficacy.
- Bioinformatic analysis identified CYP1B1 as a TAX-responsive target; its overexpression correlated with malignancy and poor prognosis.
- TAX downregulated CYP1B1, thereby inhibiting EMT progression.
Conclusions:
- This study demonstrates that TAX induces neuronal differentiation of GSCs by suppressing the CYP1B1-mediated EMT pathway.
- A novel mechanism linking CYP1B1 downregulation to GSC differentiation is uncovered.
- TAX emerges as a promising differentiation-inducing agent for GBM, offering a strategy to target stemness and EMT concurrently.
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