β2-adrenergic receptor signaling promotes neuroblastoma cell proliferation by activating autophagy

Accumulating evidence suggests the pivotal role of the sympathetic nervous system in the initiation and aggressive progression of tumors, whereas the role of beta-adrenergic receptor (beta-AR) signaling in neuroblastoma (NB) and the underlying regulatory mechanisms have not yet been well elucidated. In the present study, it was demonstrated that the expression of both beta 1-AR and beta 2-AR was significantly increased in clinical samples of NB compared with those of ganglioneuroma (GN) and ganglioneuroblastoma (GNB), and that beta 2-AR is the key beta-adrenergic receptor responsible for NB cell growth. Further investigation showed that the expression levels of the autophagy markers LC3-II, beclin-1 and unc-51-like autophagy kinase 1 (ULK1) were also elevated in NB, compared to the cases of GN and GNB. Moreover, beta 2-AR expression was found to be positively associated with autophagy markers in the clinical NB specimens. Cellular functional assays demonstrated that beta 2-AR activation promoted NB cell growth and activated the autophagy pathway. Pharmacological inhibition of autophagy with 3-methyladenine abolished beta 2-AR-induced NB cell growth. Mechanistically, beta 2-AR signaling triggers autophagy through CREB-mediated ULK1 upregulation. In conclusion, the present study uncovered a novel regulatory mechanism of beta 2-AR-activated autophagy in NB cell growth and provides a novel potential therapeutic approach for treating NB by targeting autophagy and the beta 2-AR pathway.