sr-59230a and Neuroblastoma

Oxidative stress has been implicated in a variety of neurodegenerative disorders, such as Alzheimer's and Parkinson's disease. Astrocytes play a significant role in maintaining survival of neurons by supplying antioxidants such as glutathione (GSH) to neurons. Recently, we found that noradrenaline increased the intracellular GSH concentration in astrocytes via β

Topics: Adrenergic beta-3 Receptor Agonists; Adrenergic beta-3 Receptor Antagonists; Animals; Astrocytes; Astrocytoma; Brain; Buthionine Sulfoximine; Cell Line, Tumor; Coculture Techniques; Dioxoles; Glutathione; Humans; Hydrogen Peroxide; Mice; Mice, Inbred C57BL; Neuroblastoma; Neurons; Neuroprotective Agents; Norepinephrine; Oxidative Stress; Propanolamines; Propionates; Quinolines; Receptors, Adrenergic, beta-3

Neuroblastoma (NB), the most common extracranial solid tumor in childhood, always leads to an unfavorable prognosis. β3-adrenergic receptor (β3-AR) signaling plays an important role in lipid metabolism. Although previous studies have focused mainly on the role of β2-AR in tumor cells; there are few studies about the cancer-related function of β3-AR. Herein, we showed that β3-AR expression was significantly increased in clinical NB tissue compared with that in the less malignant ganglioneuroma (GN) and ganglioneuroblastoma (GNB) tissues. Further cellular assays demonstrated that treatment of NB cells with SR59230A (a specific β3-AR antagonist) suppressed NB cells growth and colony formation, and siRNA knockdown of β3-AR expression also inhibited NB cell proliferation. The mechanistic study revealed that β3-AR knockdown and SR59230A inhibited the phosphorylation and thereby the activation of the mTOR/p70S6K pathway. Activation of the mTOR pathway with the activator MHY1485 reversed the inhibitory effect of SR59230A on NB cell growth. Above all, our study clarifies a novel regulatory role of β3-AR in NB cell growth and provides a potent therapeutic strategy for this disease by specific targeting of the β3-AR pathway.

Topics: Adrenergic beta-3 Receptor Antagonists; Cell Proliferation; Epinephrine; Gene Knockdown Techniques; Humans; Molecular Targeted Therapy; Morpholines; Neuroblastoma; Propanolamines; Receptors, Adrenergic, beta-3; Signal Transduction; TOR Serine-Threonine Kinases; Triazines; Tumor Cells, Cultured