Autophagy is an evolutionarily conserved degradative pathway by which components of the cells are degraded in the lysosome in response to stress. Beclin 1 plays a central role in autophagy. Pioneering work has indicated that the increase in cytosolic Ca(2+) can induce autophagy via the CaMKKβ-mediated activation of AMPK. Here, we demonstrate a novel signaling pathway in which CaMKKβ regulates autophagy and differentiation. We found that Ca(2+) mobilizing agents (ionomycin and EB1089) induced phosphorylation of Beclin 1 and autophagy through CaMKKβ-dependent pathway. Using In vitro kinase assay we demonstrated that CaMKKβ directly phosphorylated Beclin 1 Ser90. Moreover, autophagy induced by ionomycin or EB1089 contributed to degradation of Id1 (inhibitor of differentiation). The inhibitors of autophagy including Bafilomycin A1 and chloroquine and RNA interference of autophagy-associated gene atg 5 markedly increased the protein levels of Id1 and abrogated neuroblastoma cell differentiation. Taken together, CaMKKβ promoted autophagy by directly phosphorylating Beclin 1 at Ser90, and thus induced cell differentiation in neuroblastoma cells.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr C150.