Alantolactone Suppresses YAP Signaling and Stemness Properties in Glioblastoma Cells

Glioblastoma (GBM) remains one of the most common and lethal primary brain tumors due to its high malignancy and heterogeneity. Despite recent advances in medical technology and concerted effort to improve therapeutic methods, the prognosis of GBM still remains very poor. The poor prognosis is associated with cancer stem cells (CSCs) which hold the potential of self-renewal, and differentiation into pathogenomic heterogeneous tumor formation leading to therapeutic resistance. Therefore, targeting CSCs and their associated signaling pathways is crucial for effective treatment of GBM. In this study, we showed that alantolactone (ALT) hold the capacity to suppress stem-cell-like phenotype (SCLP) of glioblastoma cells. ALT inhibited the growth, reduced mammosphere formation and down-regulated the expression of CSCs markers such as CD133, OCT4, SOX2, and NANOG in U87 and U251 glioblastoma cells in a dose-dependent manner. Further mechanistic study showed that ALT inhibits glioma SCLP and tumor growth through repression of EGFR/MOB1/LATS1/YAP signaling pathway. These findings were further validated using in vivo xenograft mouse model. Taken together, the data provides convincing evidence of ALT-mediated inhibition of glioma SCLP and tumor growth via repression of EGFR/MOB1/ LATS1/YAP pathway and suggests ALT as a promising therapeutic drug candidate, and YAP as a potential therapeutic target for glioblastoma treatment.