GPER Mediates Activation of HIF1α/VEGF Signaling by Estrogens

Francesco, Ernestina Marianna De; Pellegrino, Michele; Santolla, Maria Francesca; Lappano, Rosamaria; Ricchio, Emilia; Abonante, Sergio; Maggiolini, Marcello

doi:10.1158/0008-5472.can-13-3590

Cited by 116 publications

(118 citation statements)

References 44 publications

(69 reference statements)

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“…Accordingly, HIF-1α was required for both the transactivation of a GPER promoter reporter gene as well as for the upregulation of GPER expression upon hypoxia (30,31). These observations were further corroborated by the involvement of HIF-1α/GPER signaling in VEGF expression toward tumor angiogenesis and progression (31,89). In addition, HIF-1α/GPER/VEGF transduction pathway was triggered in cancer cells upon exposure to copper, which showed the ability to mimic the hypoxia-mediated signaling (90).…”

Section: Gper Is Involved In Hypoxia-mediated Signalingmentioning

confidence: 80%

Recent Advances on the Role of G Protein-Coupled Receptors in Hypoxia-Mediated Signaling

Lappano

Rigiracciolo

Marco

et al. 2016

AAPS J

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Abstract. G protein-coupled receptors (GPCRs) are cell surface proteins mainly involved in signal transmission; however, they play a role also in several pathophysiological conditions. Chemically heterogeneous molecules like peptides, hormones, lipids, and neurotransmitters activate second messengers and induce several biological responses by binding to these seven transmembrane receptors, which are coupled to heterotrimeric G proteins. Recently, additional molecular mechanisms have been involved in GPCR-mediated signaling, leading to an intricate network of transduction pathways. In this regard, it should be mentioned that diverse GPCR family members contribute to the adaptive cell responses to low oxygen tension, which is a distinguishing feature of several illnesses like neoplastic and cardiovascular diseases. For instance, the G protein estrogen receptor, namely G protein estrogen receptor (GPER)/GPR30, has been shown to contribute to relevant biological effects induced by hypoxia via the hypoxia-inducible factor (HIF)-1α in diverse cell contexts, including cancer. Likewise, GPER has been found to modulate the biological outcome of hypoxic/ischemic stress in both cardiovascular and central nervous systems. Here, we describe the role exerted by GPCR-mediated signaling in low oxygen conditions, discussing, in particular, the involvement of GPER by a hypoxic microenvironment.

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Section: Gper Is Involved In Hypoxia-mediated Signalingmentioning

confidence: 80%

Recent Advances on the Role of G Protein-Coupled Receptors in Hypoxia-Mediated Signaling

Lappano

Rigiracciolo

Marco

et al. 2016

AAPS J

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“…Instead these data overwhelmingly indicate that GPER promotes anti-apoptotic and cellular survival signals that are easily linked to tumor progression. A recent study by Maggiolini and colleagues demonstrating that under hypoxic conditions both breast cancer cells and cancer-associated fibroblasts upregulate GPER expression via hypoxia inducing factor-1α (HIF-1α), suggesting that GPER is critically influenced by the tumor microenvironment [De Francesco et al, 2014]. The ability of GPER to trigger release of local EGF-like polypeptides and synthesize a provisional extracellular matrix via requisite activation of integrin α5β1 [reviewed in Filardo, 2011] are a further reminder that GPER mediates its affects within the tumor microenvironment, and are likely important for the survival of infiltrating breast cancer cells that extravasate from mammary gland epithelia.…”

Section: A C C E P T E D Accepted Manuscriptmentioning

confidence: 99%

“…14 investigation to determine whether low oxygen content or tissue injury during reperfusion provokes an increase in GPER expression similar to that observed in in breast cancer cells and cancer-associated fibroblasts [De Francesco et al, 2014]. Finally, GPER may have clinical benefit in limiting brain injury induced by cardiac arrest as demonstrated by the neuroprotective role of G1 in a model of global cerebral ischemia as measured by reduced neuronal injury in the hippocampal CA1 region and striatum [Kosaka et al, 2012].…”

Section: A C C E P T E D Accepted Manuscriptmentioning

confidence: 99%

The G-protein coupled estrogen receptor, GPER: The inside and inside-out story

Gaudet

Cheng

Christensen

et al. 2015

Molecular and Cellular Endocrinology

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“…The ligand activation of GPER stimulates a transduction network which includes the epidermal growth factor receptor (EGFR), crucial intracellular pathways like phosphatidylinositol 3-kinase/protein kinase B (PI3K/Akt), mitogen-activated protein kinase/extracellular regulated protein kinase (MAPK/ERK), calcium mobilization, and others in both normal and malignant cells (6). Notably, GPER activation triggers a peculiar gene signature involved in cancer cell growth, migration, and angiogenesis (6)(7)(8)(9). In accordance with these findings, previous studies have associated GPER expression with negative clinical features and poor survival rates in a variety of tumors (10)(11)(12).…”

Section: Introductionmentioning

confidence: 99%

Macromolecular Modelling and Docking Simulations for the Discovery of Selective GPER Ligands

Rosano

Ponassi

Santolla

et al. 2015

AAPS J

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Abstract. Estrogens influence multiple physiological processes and are implicated in many diseases as well. Cellular responses to estrogens are mainly mediated by the estrogen receptors (ER)α and ERβ, which act as ligand-activated transcription factors. Recently, a member of the G proteincoupled receptor (GPCR) superfamily, namely GPER/GPR30, has been identified as a further mediator of estrogen signalling in different pathophysiological conditions, including cancer. Today, computational methods are commonly used in all areas of health science research. Among these methods, virtual ligand screening has become an established technique for hit discovery and optimization. The absence of an established three-dimensional structure of GPER promoted studies of structure-based drug design in order to build reliable molecular models of this receptor. Here, we discuss the results obtained through the structure-based virtual ligand screening for GPER, which allowed the identification and synthesis of different selective agonist and antagonist moieties. These compounds led significant advances in our understanding of the GPER function at the cellular, tissue, and organismal levels. In particular, selective GPER ligands were critical toward the evaluation of the role elicited by this receptor in several pathophysiological conditions, including cancer. Considering that structure-based approaches are fundamental in drug discovery, future research breakthroughs with the aid of computer-aided molecular design and chemobioinformatics could generate a new class of drugs that, acting through GPER, would be useful in a variety of diseases as well as in innovative anticancer strategies.

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GPER Mediates Activation of HIF1α/VEGF Signaling by Estrogens

Cited by 116 publications

References 44 publications

Recent Advances on the Role of G Protein-Coupled Receptors in Hypoxia-Mediated Signaling

Recent Advances on the Role of G Protein-Coupled Receptors in Hypoxia-Mediated Signaling

The G-protein coupled estrogen receptor, GPER: The inside and inside-out story

Macromolecular Modelling and Docking Simulations for the Discovery of Selective GPER Ligands

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