β2-adrenergic receptor signaling promotes neuroblastoma cell proliferation by activating autophagy
β2-adrenergic receptor signaling promotes neuroblastoma cell proliferation by activating autophagy
复制标题
β2-肾上腺素能受体信号通过激活自噬促进神经母细胞瘤细胞增殖
DOI：
10.3892/or.2019.7266
复制
发表时间：
2019-10-01
期刊：
影响因子：
4.2
通讯作者：
Yang, Xia
中科院分区：
文献类型：
--
作者：
Deng, Jing;Jiang, Ping;Yang, Xia
越来越多的证据表明，交感神经系统在肿瘤的发生和侵袭发展中起着关键作用，而β-肾上腺素能受体(beta-AR)信号在神经母细胞瘤中的作用及其潜在的调控机制尚未得到很好的阐明。本研究表明，与神经节细胞瘤(GN)和神经节神经母细胞瘤(GNB)相比，神经母细胞瘤中β_1-AR和β_2-AR的表达均显著增加，并且β_2-AR是促进NB细胞生长的关键β-肾上腺素能受体。进一步研究发现，自噬标志物LC3-II、BECLIN-1和UNC-51样自噬蛋白1(ULK1)在NB中的表达水平也高于GN和GNB。此外，在临床NB标本中，β2-AR的表达与自噬标志物呈正相关。细胞功能分析表明，β2-AR的激活促进了NB细胞的生长并激活了自噬途径。3-甲基腺嘌呤抑制自噬的药理作用可阻断β2-AR诱导的NB细胞生长。机制上，β2-AR信号通过CREB介导的ULK1上调触发自噬。综上所述，本研究揭示了β2-AR激活的自噬在NB细胞生长中的一种新的调控机制，并为通过靶向自噬和β2-AR途径治疗NB提供了一种新的潜在的治疗途径。
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.