β3-adrenoreceptor blockade reduces tumor growth and increases neuronal differentiation in neuroblastoma via SK2/S1P2 modulation

被引:38
作者
Bruno, Gennaro [1 ,2 ]
Cencetti, Francesca [3 ]
Pini, Alessandro [4 ]
Tondo, Annalisa [2 ]
Cuzzubbo, Daniela [2 ]
Fontani, Filippo [1 ,2 ]
Strinna, Vanessa [2 ]
Buccoliero, Anna Maria [5 ]
Casazza, Gabriella [6 ]
Donati, Chiara [3 ]
Filippi, Luca [7 ]
Bruni, Paola [3 ]
Favre, Claudio [2 ]
Calvani, Maura [2 ]
机构
[1] Univ Florence, Dept Hlth Sci, Florence, Italy
[2] A Meyer Univ, Dept Paediat Haematol Oncol, Childrens Hosp, Florence, Italy
[3] Univ Florence, Dept Expt & Clin Biomed Sci Mario Serio, Florence, Italy
[4] Univ Florence, Dept Expt & Clin Med, Florence, Italy
[5] A Meyer Univ, Pathol Unit, Childrens Hosp, Florence, Italy
[6] Santa Chiara Hosp, Pediat Hematol Oncol & Bone Marrow Transplant Uni, Pisa, Italy
[7] A Meyer Univ, Med Surg Feto Neonatal Dept, Neonatal Intens Care Unit, Childrens Hosp, Florence, Italy
关键词
ACUTE LYMPHOBLASTIC-LEUKEMIA; HUMAN-MELANOMA; MESSENGER-RNA; BETA-BLOCKERS; COLON-CANCER; BONE-MARROW; CELL LINES; EXPRESSION; CLASSIFICATION; ADRENOCEPTORS;
D O I
10.1038/s41388-019-0993-1
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Neuroblastoma (NB) is the most frequently observed among extracranial pediatric solid tumors. It displays an extreme clinical heterogeneity, in particular for the presentation at diagnosis and response to treatment, often depending on cancer cell differentiation/stemness. The frequent presence of elevated hematic and urinary levels of catecholamines in patients affected by NB suggests that the dissection of adrenergic system is crucial for a better understanding of this cancer. beta 3-adrenoreceptor (beta 3-AR) is the last identified member of adrenergic receptors, involved in different tumor conditions, such as melanoma. Multiple studies have shown that the dysregulation of the bioactive lipid sphingosine 1-phosphate (S1P) metabolism and signaling is involved in many pathological diseases including cancer. However, whether S1P is crucial for NB progression and aggressiveness is still under investigation. Here we provide experimental evidence that beta 3-AR is expressed in NB, both human specimens and cell lines, where it is critically involved in the activation of proliferation and the regulation between stemness/differentiation, via its functional cross-talk with sphingosine kinase 2 (SK2)/S1P receptor 2 (S1P(2)) axis. The specific antagonism of beta 3-AR by SR59230A inhibits NB growth and tumor progression, by switching from stemness to cell differentiation both in vivo and in vitro through the specific blockade of SK2/S1P(2) signaling.
引用
收藏
页码:368 / 384
页数:17
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