Beta-Elemene Promotes The Senescence Of Glioma Cells Through Regulating Yap-Cdk6 Signaling

Glioma is currently the most widespread and malignant primary intracranial tumor, which is characterized by high heterogeneity and high fatality rates. beta-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 beta-elemene in glioma senescence remains unknown. In the present study, we found that a low concentration of beta-elemene (10 mu g/mL) induced senescence in glioma cells, including reduction of cell proliferation, hypertrophic morphology, increase of senescence-associated beta-galactosidase (SA-beta-Gal) activity, upregulation of several senescence-associated genes such as p16, p53 and NF-kappa B, and downregulation of Lamin B1. However, a high concentration of beta-elemene induced apoptosis in glioma cells. Treatment with beta-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 beta-elemene. The overexpression of YAP and CDK6 significantly rescued beta-elemene-induced senescence in glioma cells. Finally, beta-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 beta-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.