STAT3 Suppresses The AMPKα-ULK1-Dependent Induction of Autophagy In Glioblastoma Cells

Despite advances in molecular characterization, glioblastoma (GBM) remains the most lethal type of brain tumor with high mortality rates in both pediatric and adult patients. The signal transducer and activator of transcription 3 (STAT3), is an important oncogenic driver of GBM. Although STAT3 reportedly plays a role in autophagy of some cells, its role in cancer cell autophagy remains unclear. In this study, we found STAT3 phosphorylation on Y705 and S727 residues, acetylation on K685, and tri-methylation on K180 was constitutive in GBM cell lines. Tyrosine phosphorylation of STAT3 in MT330 GBM cells suppresses autophagy, whereas knockout (KO) of STAT3 increases ULK1 gene expression, increases TSC2-AMPKa-ULK1 signaling and Prom1/CD133 expression, decreases p62 gene expression and accumulation, and increases lysosomal Cathepsin D processing, leading to the stimulation of autophagic flux. Rescue of STAT3-KO cells by the enforced expression of wild-type (WT) STAT3 reverses these pathways and inhibits autophagic flux. Conversely, expression of Y705F-STAT3 and S727A-STAT3 mutants in STAT3-KO cells did not suppress autophagy. Inhibition of ULK1 activity (by MRT68921) or its expression (by siRNA) in STAT3-KO cells inhibits autophagy flux and sensitizes cells to apoptosis. Taken together, our findings suggest that both STAT3 serine and tyrosine phosphorylation play critical roles in STAT3-dependent autophagy in GBM and the potential of targeting this pathway to treat GBM.