β-elemene promotes the senescence of glioma cells through regulating YAP-CDK6 signaling
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Published on: March 27, 2020
Danlu Yang1,2, Xingxing Xu2, Xin Wang1
1Key Laboratory of β-elemene Anti-cancer Medicine of Zhejiang Province and Holistic Integrative Pharmacy Institutes, and Department of Neurosurgery, The Affiliated Hospital, Hangzhou Normal University Hangzhou 311121, Zhejiang, China.
Abstract:
Glioma is currently the most widespread and malignant primary intracranial tumor, which is characterized by high heterogeneity and high fatality rates. β-elemene, which is a bioactive compound extracted from a Chinese herb, Curcuma wenyujin, has been reported to reduce resistance of chemotherapeutic drugs and induce apoptosis in tumor cells. However, the role and mechanisms of β-elemene in glioma senescence remains unknown. In the present study, we found that a low concentration of β-elemene (10 μg/mL) induced senescence in glioma cells, including reduction of cell proliferation, hypertrophic morphology, increase of senescence-associated β-galactosidase (SA-β-Gal) activity, upregulation of several senescence-associated genes such as p16, p53 and NF-κB, and downregulation of Lamin B1. However, a high concentration of β-elemene induced apoptosis in glioma cells. Treatment with β-elemene caused a marked down-regulation of Yes-associated protein (YAP) expression in glioma cells, which is a key transcriptional co-activator in multiple cancers. Moreover, cyclin dependent kinase 6 (CDK6), which is a known downstream target of YAP, was decreased in glioma cells that treated with β-elemene. The overexpression of YAP and CDK6 significantly rescued β-elemene-induced senescence in glioma cells. Finally, β-elemene treatment also induced the senescence of glioma cells in glioma xenograft model through inactivation of YAP-CDK6 pathways, which might inhibit the glioma growth. Taken together, these results reveal a previously unknown role of β-elemene in glioma cell senescence in vitro and in vivo that is associated with YAP-CDK6 signaling pathway, which will enhance our understanding of glioma cell senescence, and provide novel strategies for the treatment of gliomas.
Insights
Beta-elemene induces glioma cell senescence at low concentrations by downregulating the YAP-CDK6 pathway. This finding offers new therapeutic strategies for glioma treatment by targeting senescence.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Research
Background:
- Glioma is a prevalent and aggressive brain tumor with high mortality.
- Beta-elemene, derived from Curcuma wenyujin, shows potential in cancer therapy by overcoming drug resistance and inducing apoptosis.
- The role of beta-elemene in inducing glioma cell senescence remains unexplored.
Purpose of the Study:
- To investigate the effects and underlying mechanisms of beta-elemene on glioma cell senescence.
- To determine the involvement of the YAP-CDK6 signaling pathway in beta-elemene-induced senescence.
Main Methods:
- Glioma cells were treated with varying concentrations of beta-elemene.
- Senescence was assessed through cell proliferation, morphology, SA-β-Gal activity, and gene expression (p16, p53, NF-κB, Lamin B1).
- The expression of YAP and CDK6 was analyzed, and their roles in beta-elemene-induced senescence were evaluated in vitro and in vivo using a xenograft model.
Main Results:
- Low-concentration beta-elemene induced senescence in glioma cells, characterized by reduced proliferation, altered morphology, increased SA-β-Gal activity, and specific gene expression changes.
- High-concentration beta-elemene induced apoptosis.
- Beta-elemene treatment downregulated YAP and CDK6 expression, key players in glioma progression.
- Overexpression of YAP and CDK6 partially rescued beta-elemene-induced senescence.
- In vivo studies confirmed beta-elemene induced glioma cell senescence via YAP-CDK6 pathway inactivation, inhibiting tumor growth.
Conclusions:
- Beta-elemene induces glioma cell senescence at low concentrations through the inactivation of the YAP-CDK6 signaling pathway.
- This study elucidates a novel mechanism for beta-elemene in glioma, distinct from apoptosis induction.
- Targeting the YAP-CDK6 pathway with beta-elemene presents a promising therapeutic strategy for glioma.
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