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Pleiotropic Effect of β-Adrenergic Receptors in Human Cancers and Other Human Diseases II

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Oncology".

Deadline for manuscript submissions: closed (25 May 2023) | Viewed by 15343

Special Issue Editor

Dr. Claudio Favre

E-Mail Website
Guest Editor
Division of Pediatric Oncology/Hematology, Meyer University Children’s Hospital, 50139 Florence, Italy
Interests: β-adrenergic receptors in pediatric cancer; blood malignancy; innovative therapy nutraceutical approach in cancer therapy
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Recently, a growing number of studies have suggested that bio-behavioral factors, especially various stress-related persistent stimulations, might accelerate cancer progression, which is mainly due to β-adrenergic system activation.

β-Adrenergic receptors on the tumor and stromal cells are activated by catecholamines such as adrenaline and noradrenaline. Based largely on retrospective analyses, pharmacological inhibition of the β-adrenergic receptors using beta blockers has shown clinical anticancer efficacy in many human cancers. In particular, recent advances have evidenced a role of the β3-adrenoreceptor in different pathways involved in cancer progression, apoptosis, antioxidant action, metastasis, and microenvironmental transformation.

This Special Issue on “Pleiotropic Effect of β-Adrenergic Receptors in Human Cancers and Other Human Diseases II” of the International Journal of Molecular Sciences aims at providing new insights into the various functions of β-Adrenergic receptors in the several aspects of cancer progression mechanisms.

Dr. Claudio Favre
Guest Editor

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Keywords

  • tumor microenvironment
  • β3-adrenoreceptor
  • β2-adrenoreceptor
  • metastasis
  • antioxidant activity
  • cancer

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Published Papers (5 papers)

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Research

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17 pages, 2786 KiB  
Article
Blockade of ß-Adrenergic Receptors by Nebivolol Enables Tumor Control Potential for Uveal Melanoma in 3D Tumor Spheroids and 2D Cultures
by Lina S. Farhoumand, Hongtao Liu, Theodora Tsimpaki, Ulrike B. Hendgen-Cotta, Tienush Rassaf, Nikolaos E. Bechrakis, Miltiadis Fiorentzis and Utta Berchner-Pfannschmidt
Int. J. Mol. Sci. 2023, 24(6), 5894; https://doi.org/10.3390/ijms24065894 - 20 Mar 2023
Cited by 7 | Viewed by 2533
Abstract
Uveal melanoma (UM) is the most common primary cancer of the eye in adults. A new systemic therapy is needed to reduce the high metastasis and mortality rate. As β-blockers are known to have anti-tumor effects on various cancer entities, this study focuses [...] Read more.
Uveal melanoma (UM) is the most common primary cancer of the eye in adults. A new systemic therapy is needed to reduce the high metastasis and mortality rate. As β-blockers are known to have anti-tumor effects on various cancer entities, this study focuses on investigating the effect of β1-selective blockers atenolol, celiprolol, bisoprolol, metoprolol, esmolol, betaxolol, and in particular, nebivolol on UM. The study was performed on 3D tumor spheroids as well as 2D cell cultures, testing tumor viability, morphological changes, long-term survival, and apoptosis. Flow cytometry revealed the presence of all three β-adrenoceptors with a dominance of β2-receptors on cell surfaces. Among the blockers tested, solely nebivolol concentration-dependently decreased viability and altered 3D tumor spheroid structure. Nebivolol blocked the repopulation of cells spreading from 3D tumor spheroids, indicating a tumor control potential at a concentration of ≥20 µM. Mechanistically, nebivolol induced ATP depletion and caspase-3/7 activity, indicating that mitochondria-dependent signaling is involved. D-nebivolol or nebivolol combined with the β2-antagonist ICI 118.551 displayed the highest anti-tumor effects, suggesting a contribution of both β1- and β2-receptors. Thus, the present study reveals the tumor control potential of nebivolol in UM, which may offer a perspective for co-adjuvant therapy to reduce recurrence or metastasis. Full article
(This article belongs to the Special Issue Pleiotropic Effect of β-Adrenergic Receptors in Human Cancers and Other Human Diseases II)
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13 pages, 2344 KiB  
Article
β3 Adrenergic Receptor Agonist Mirabegron Increases AQP2 and NKCC2 Urinary Excretion in OAB Patients: A Pleiotropic Effect of Interest for Patients with X-Linked Nephrogenic Diabetes Insipidus
by Serena Milano, Fatima Maqoud, Monica Rutigliano, Ilenia Saponara, Monica Carmosino, Andrea Gerbino, Giuseppe Lucarelli, Michele Battaglia, Maria Svelto and Giuseppe Procino
Int. J. Mol. Sci. 2023, 24(2), 1136; https://doi.org/10.3390/ijms24021136 - 6 Jan 2023
Cited by 2 | Viewed by 2146
Abstract
We previously reported the novel finding that β3-AR is functionally expressed in the renal tubule and shares its cellular localization with the vasopressin receptor AVPR2, whose physiological stimulation triggers antidiuresis by increasing the plasma membrane expression of the water channel AQP2 and the [...] Read more.
We previously reported the novel finding that β3-AR is functionally expressed in the renal tubule and shares its cellular localization with the vasopressin receptor AVPR2, whose physiological stimulation triggers antidiuresis by increasing the plasma membrane expression of the water channel AQP2 and the NKCC2 symporter in renal cells. We also showed that pharmacologic stimulation of β3-AR is capable of triggering antidiuresis and correcting polyuria, in the knockout mice for the AVPR2 receptor, the animal model of human X-linked nephrogenic diabetes insipidus (XNDI), a rare genetic disease still missing a cure. Here, to demonstrate that the same response can be evoked in humans, we evaluated the effect of treatment with the β3-AR agonist mirabegron on AQP2 and NKCC2 trafficking, by evaluating their urinary excretion in a cohort of patients with overactive bladder syndrome, for the treatment of which the drug is already approved. Compared to baseline, treatment with mirabegron significantly increased AQP2 and NKCC2 excretion for the 12 weeks of treatment. This data is a step forward in corroborating the hypothesis that in patients with XNDI, treatment with mirabegron could bypass the inactivation of AVPR2, trigger antidiuresis and correct the dramatic polyuria which is the main hallmark of this disease. Full article
(This article belongs to the Special Issue Pleiotropic Effect of β-Adrenergic Receptors in Human Cancers and Other Human Diseases II)
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14 pages, 2161 KiB  
Article
Activation of β-Adrenoceptors Promotes Lipid Droplet Accumulation in MCF-7 Breast Cancer Cells via cAMP/PKA/EPAC Pathways
by Dany Silva, Katarzyna Kacprzak, Clara Quintas, Jorge Gonçalves and Paula Fresco
Int. J. Mol. Sci. 2023, 24(1), 767; https://doi.org/10.3390/ijms24010767 - 1 Jan 2023
Cited by 5 | Viewed by 3177
Abstract
Physiologically, β-adrenoceptors are major regulators of lipid metabolism, which may be reflected in alterations in lipid droplet dynamics. β-adrenoceptors have also been shown to participate in breast cancer carcinogenesis. Since lipid droplets may be seen as a hallmark of cancer, the present study [...] Read more.
Physiologically, β-adrenoceptors are major regulators of lipid metabolism, which may be reflected in alterations in lipid droplet dynamics. β-adrenoceptors have also been shown to participate in breast cancer carcinogenesis. Since lipid droplets may be seen as a hallmark of cancer, the present study aimed to investigate the role of β-adrenoceptors in the regulation of lipid droplet dynamics in MCF-7 breast cancer cells. Cells were treated for up to 72 h with adrenaline (an endogenous adrenoceptor agonist), isoprenaline (a non-selective β-adrenoceptor agonist) and salbutamol (a selective β2-selective agonist), and their effects on lipid droplets were evaluated using Nile Red staining. Adrenaline or isoprenaline, but not salbutamol, caused a lipid-accumulating phenotype in the MCF-7 cells. These effects were significantly reduced by selective β1- and β3-antagonists (10 nM atenolol and 100 nM L-748,337, respectively), indicating a dependence on both β1- and β3-adrenoceptors. These effects were dependent on the cAMP signalling pathway, involving both protein kinase A (PKA) and cAMP-dependent guanine-nucleotide-exchange (EPAC) proteins: treatment with cAMP-elevating agents (forskolin or 8-Br-cAMP) induced lipid droplet accumulation, whereas either 1 µM H-89 or 1 µM ESI-09 (PKA or EPAC inhibitors, respectively) abrogated this effect. Taken together, the present results demonstrate the existence of a β-adrenoceptor-mediated regulation of lipid droplet dynamics in breast cancer cells, likely involving β1- and β3-adrenoceptors, revealing a new mechanism by which adrenergic stimulation may influence cancer cell metabolism. Full article
(This article belongs to the Special Issue Pleiotropic Effect of β-Adrenergic Receptors in Human Cancers and Other Human Diseases II)
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Review

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28 pages, 4821 KiB  
Review
β-Adrenoreceptors as Therapeutic Targets for Ocular Tumors and Other Eye Diseases—Historical Aspects and Nowadays Understanding
by Elsa Wilma Böhm, Bernhard Stoffelns and Adrian Gericke
Int. J. Mol. Sci. 2023, 24(5), 4698; https://doi.org/10.3390/ijms24054698 - 28 Feb 2023
Cited by 4 | Viewed by 4016
Abstract
β-adrenoreceptors (ARs) are members of the superfamily of G-protein-coupled receptors (GPCRs), and are activated by catecholamines, such as epinephrine and norepinephrine. Three subtypes of β-ARs (β1, β2, and β3) have been identified with different distributions among ocular [...] Read more.
β-adrenoreceptors (ARs) are members of the superfamily of G-protein-coupled receptors (GPCRs), and are activated by catecholamines, such as epinephrine and norepinephrine. Three subtypes of β-ARs (β1, β2, and β3) have been identified with different distributions among ocular tissues. Importantly, β-ARs are an established target in the treatment of glaucoma. Moreover, β-adrenergic signaling has been associated with the development and progression of various tumor types. Hence, β-ARs are a potential therapeutic target for ocular neoplasms, such as ocular hemangioma and uveal melanoma. This review aims to discuss the expression and function of individual β-AR subtypes in ocular structures, as well as their role in the treatment of ocular diseases, including ocular tumors. Full article
(This article belongs to the Special Issue Pleiotropic Effect of β-Adrenergic Receptors in Human Cancers and Other Human Diseases II)
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20 pages, 1061 KiB  
Review
ß-Adrenoreceptors in Human Cancers
by Zoltan Kraboth and Bernadette Kalman
Int. J. Mol. Sci. 2023, 24(4), 3671; https://doi.org/10.3390/ijms24043671 - 12 Feb 2023
Cited by 4 | Viewed by 2747
Abstract
Cancer is the leading cause of death and represents a significant economic burden worldwide. The numbers are constantly growing as a result of increasing life expectancy, toxic environmental factors, and adoption of Western lifestyle. Among lifestyle factors, stress and the related signaling pathways [...] Read more.
Cancer is the leading cause of death and represents a significant economic burden worldwide. The numbers are constantly growing as a result of increasing life expectancy, toxic environmental factors, and adoption of Western lifestyle. Among lifestyle factors, stress and the related signaling pathways have recently been implicated in the development of tumors. Here we present some epidemiological and preclinical data concerning stress-related activation of the ß-adrenoreceptors (ß-ARs), which contributes to the formation, sequential transformation, and migration of different tumor cell types. We focused our survey on research results for breast and lung cancer, melanoma, and gliomas published in the past five years. Based on the converging evidence, we present a conceptual framework of how cancer cells hijack a physiological mechanism involving ß-ARs toward a positive modulation of their own survival. In addition, we also highlight the potential contribution of ß-AR activation to tumorigenesis and metastasis formation. Finally, we outline the antitumor effects of targeting the ß-adrenergic signaling pathways, methods for which primarily include repurposed ß-blocker drugs. However, we also call attention to the emerging (though as yet largely explorative) method of chemogenetics, which has a great potential in suppressing tumor growth either by selectively modulating neuronal cell groups involved in stress responses affecting cancer cells or by directly manipulating specific (e.g., the ß-AR) receptors on a tumor and its microenvironment. Full article
(This article belongs to the Special Issue Pleiotropic Effect of β-Adrenergic Receptors in Human Cancers and Other Human Diseases II)
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