Casticin induces apoptosis and cytoprotective autophagy while inhibiting stemness involving Akt/mTOR and JAK2/STAT3 pathways in glioblastoma.

Abstract

Glioblastoma (GBM) is the most common malignant glioma. However, the current systemic drugs cannot completely cure GBM. Casticin is a methoxylated flavonol compound isolated from a traditional Chinese medicine Vitex rotundifolia L.f. and exhibits a strong antitumor activity in multiple human malignancies. This study was aimed to explore the effects and underlying mechanisms of casticin in GBM. The MTT assay and colony formation was used to evaluate the casticin-induced cell viability in GBM cells. Apoptosis was assessed by ANNEXIV/PI staining assay. Autophagy was analyzed by transmission electron microscopy and immunofluorescence assays. GBM stem cell (GSC) was analyzed by tumor-sphere formation assay and ALDEFLUOR assay. The anti-GBM effect of casticin was also determined by the U87MG xenograft model. Casticin inhibited tumor cell growth in vitro and in vivo, as well as significantly induced apoptosis and autophagy. Autophagy inhibition augmented casticin-induced apoptosis. Casticin also reduced the GSC population by suppressing Oct4, Nanog, and Sox2. Mechanistically, casticin inhibited Akt/mTOR and JAK2/STAT3 signal pathways. The antitumor effect of casticin in GBM was demonstrated by inducing apoptosis, autophagy, and reducing population of GSCs; thus, it may be a potential GBM therapeutic agent for future clinical usage.