The early phases of embryonic development and cancer share similar strategies to improve their survival in an inhospitable environment: both proliferate in a hypoxic and catecholamine-rich context, increasing aerobic glycolysis. Recent studies show that β3-adrenergic receptor (β3-AR) is involved in tumor progression, playing an important role in metastasis. Among β-adrenergic receptors, β3-AR is the last identified member of this family, and it is involved in cancer cell survival and induction of stromal reactivity in the tumor microenvironment. β3-AR is well known as a strong activator of uncoupling protein 1 (UCP1) in brown fat tissue. Interestingly, β3-AR is strongly expressed in early embryo development and in many cancer tissues. Induction of uncoupling protein 2 (UCP2) has been related to cancer metabolic switch, leading to accelerated glycolysis and reduced mitochondrial activity. In this study, for the first time, we demonstrate that β3-AR is able to promote this metabolic shift in both cancer and embryonic stem cells, inducing specific glycolytic cytoplasmic enzymes and a sort of mitochondrial dormancy through the induction of UCP2. The β3-AR/UCP2 axis induces a strong reduction of mitochondrial activity by reducing ATP synthesis and mitochondrial reactive oxygen species (mtROS) content. These effects are reverted by SR59230A, the specific β3-AR antagonist, causing an increase in mtROS. The increased level of mtROS is neutralized by a strong antioxidant activity in embryonic stem cells, but not in cancer stem cells, where it causes a dramatic reduction in tumor cell viability. These results lead to the possibility of a selective antitumor therapeutic use of SR59230A. Notably, we demonstrate the presence of β3-AR within the mitochondrial membrane in both cell lines, leading to the control of mitochondrial dormancy.

β3-Adrenoreceptors Control Mitochondrial Dormancy in Melanoma and Embryonic Stem Cells

Massimo Dal Monte;Luca Filippi
2018

Abstract

The early phases of embryonic development and cancer share similar strategies to improve their survival in an inhospitable environment: both proliferate in a hypoxic and catecholamine-rich context, increasing aerobic glycolysis. Recent studies show that β3-adrenergic receptor (β3-AR) is involved in tumor progression, playing an important role in metastasis. Among β-adrenergic receptors, β3-AR is the last identified member of this family, and it is involved in cancer cell survival and induction of stromal reactivity in the tumor microenvironment. β3-AR is well known as a strong activator of uncoupling protein 1 (UCP1) in brown fat tissue. Interestingly, β3-AR is strongly expressed in early embryo development and in many cancer tissues. Induction of uncoupling protein 2 (UCP2) has been related to cancer metabolic switch, leading to accelerated glycolysis and reduced mitochondrial activity. In this study, for the first time, we demonstrate that β3-AR is able to promote this metabolic shift in both cancer and embryonic stem cells, inducing specific glycolytic cytoplasmic enzymes and a sort of mitochondrial dormancy through the induction of UCP2. The β3-AR/UCP2 axis induces a strong reduction of mitochondrial activity by reducing ATP synthesis and mitochondrial reactive oxygen species (mtROS) content. These effects are reverted by SR59230A, the specific β3-AR antagonist, causing an increase in mtROS. The increased level of mtROS is neutralized by a strong antioxidant activity in embryonic stem cells, but not in cancer stem cells, where it causes a dramatic reduction in tumor cell viability. These results lead to the possibility of a selective antitumor therapeutic use of SR59230A. Notably, we demonstrate the presence of β3-AR within the mitochondrial membrane in both cell lines, leading to the control of mitochondrial dormancy.
Calvani, Maura; Cavallini, Lorenzo; Tondo, Annalisa; Spinelli, Valentina; Ricci, Luisa; Pasha, Amada; Bruno, Gennaro; Buonvicino, Daniela; Bigagli, Elisabetta; Vignoli, Marina; Bianchini, Francesca; Sartiani, Laura; Lodovici, Maura; Semeraro, Roberto; Fontani, Filippo; De Logu, Francesco; DAL MONTE, Massimo; Chiarugi, Paola; Favre, Claudio; Filippi, Luca
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Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/11568/934577
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