Abstract
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. β3-adrenoreceptor (β3-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 β3-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 (S1P2) axis. The specific antagonism of β3-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/S1P2 signaling.
Highlights
These authors contributed : Gennaro Bruno, Francesca CencettiThese authors jointly supervised this work: Claudio Favre, Maura Calvani
Our data demonstrate that in NB cancer, β3-AR blockade leads to a switch from a proliferative to a neuronal differentiation state, and that this effect is completely abolished when the S1P receptor 2 (S1P2) receptor is triggered by a selective agonist. These results prove the existence of a functional cross talk between β3-AR and sphingosine 1-phosphate (S1P) signaling in regulating the proliferation/differentiation balance in NB cells
BRL37344 increased the CD34 expression in neurospheres, but when sphingosine kinase 2 (SK2) activity was pharmacologically blocked by ABC294640, the expression of the stem marker was similar to the control condition (Fig. 5d), leading to the conclusion that SK2 was involved in the potentiation of stemness downstream of β3-AR in NB
Summary
NB arises from a sympathoadrenal lineage progenitor of the neural crest during development It is a heterogeneous malignancy with prognosis ranging from good outcome in low-risk disease to poor survival in high-risk, depending on tumor biology and clinical presentation at diagnosis. Recent studies have shown that the use of selective β3-AR antagonists in melanoma was effective in reducing tumor growth via direct antitumoral effects [18] and by affecting tumor microenvironment reactivity [19]. These results demonstrate that the β3AR is far more widespread in tumors than previously thought, suggesting that it could play an important role in cancer biology. We provide experimental evidence that SK2/S1P2 axis is responsible for β3-AR-dependent effects in NB and provide the molecular rationale to consider β3AR/SK2/S1P2 as a promising therapeutic target for NB treatment
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