Estriol acts as a GPR30 antagonist in estrogen receptor-negative breast cancer cells

Lappano, Rosamaria; Rosano, Camillo; Marco, Paola De; Francesco, Ernestina Marianna De; Pezzi, Vincenzo; Maggiolini, Marcello

doi:10.1016/j.mce.2010.02.006

Cited by 110 publications

(99 citation statements)

References 62 publications

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“…Following previous studies on the ability of estrogens to activate GPER signalling, a first approach based on computational techniques was adopted by our group with the aim to visualize the binding mode of estriol (E3) (27). Different from the almost similar steroid E2 that acts as a GPER and ER agonist, E3 displays an antagonist action through GPER.…”

Section: Endogenous and Exogenous Gper Ligand Binding Modesmentioning

confidence: 99%

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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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Section: Endogenous and Exogenous Gper Ligand Binding Modesmentioning

confidence: 99%

“…Using the aforementioned approaches, several different natural and synthetic ligands of GPER (Fig. 1) have been identified along with their binding modes as resulting from docking simulations (13,(24)(25)(26)(27)(28)(29)(30)(31)(32)(33)(34)(35).…”

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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“…Moreover, it has been shown that the activation of the Gα s protein by GPER is responsible for the estrogen, phyto-and xenoestrogens stimulation of adenylate cyclase and the ensuing increase in cAMP in breast cancer cells [140,141] . The signaling events upon GPER activation by both estrogens and notably ER antagonists can lead to gene transcription as well as to the growth and migration in diverse hormone-sensitive tumors like breast, endometrial and ovarian cancer [142][143][144][145][146][147][148][149] . Notably, GPER was also involved in the stimulatory effects elicited by estrogens and ER antagonists in cancer-associated fibroblasts [147,150] .…”

Section: Gpcrs Activated By Hormonesmentioning

confidence: 99%

GPCRs and cancer

Lappano

2012

Acta Pharmacol Sin

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G-protein-coupled receptors (GPCRs), which represent the largest gene family in the human genome, play a crucial role in multiple physiological functions as well as in tumor growth and metastasis. For instance, various molecules like hormones, lipids, peptides and neurotransmitters exert their biological effects by binding to these seven-transmembrane receptors coupled to heterotrimeric G-proteins, which are highly specialized transducers able to modulate diverse signaling pathways. Furthermore, numerous responses mediated by GPCRs are not dependent on a single biochemical route, but result from the integration of an intricate network of transduction cascades involved in many physiological activities and tumor development. This review highlights the emerging information on the various responses mediated by a selected choice of GPCRs and the molecular mechanisms by which these receptors exert a primary action in cancer progression. These findings provide a broad overview on the biological activity elicited by GPCRs in tumor cells and contribute to the identification of novel pharmacological approaches for cancer patients.

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“…Estriol (E3) is one form of estrogen metabolized from E2 through E1 in the ovaries of women and E3 is the principal estrogen produced by the placenta during pregnancy when it achieves even a 1000-fold increase (Lappano et al, 2010). However, E3 is assumed to be less potent than E2 and E1 at similar concentrations.…”

Section: Introductionmentioning

confidence: 99%

Long-term exposure investigating the estrogenic potency of estriol in Japanese medaka (Oryzias latipes)

Lei

Kang

et al. 2014

Comparative Biochemistry and Physiology Part C: Toxicology &

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The growth, development, and ERα and Vtg-I gene expressions of Japanese ricefish (Oryzias latipes; medaka) exposed to different concentrations of estriol (E3), including one environmentally relevant concentration, during embryo-adult life stages were evaluated. At the early life stage, fertilized eggs were exposed to 5, 50, 500, 5000 ng/L E3 for 15 days, and the hatched fry were exposed continuously to the same concentrations for an additional 15 days. Exposure to 500 and 5000 ng/L E3 resulted in adverse effects on hatchability and time to hatching. At 5000 ng/L, the gross abnormality rate was increased and the number of females that hatched was twice that of males. When the fish were exposed to 5-5000 ng/L E3 for further 60 days, the male hepatosomatic index (HSI) was increased at 5000 ng/L. The female gonadosomatic index (GSI) was decreased at 500 and 5000 ng/L E3, while the male GSI at 5000 ng/L E3 was increased and sex reversal was also found at this concentration. Quantitative RT-PCR showed that the hepatic vitellogenin-I (Vtg-I) genes were up-regulated in females at 500 and 5000 ng/L E3 and in males at all E3 concentrations, whereas E3 did not affect estrogen receptor α (ERα) mRNA transcription. These results showed that E3 at environmental concentration of 5 ng/L has no adverse effects on growth and development of the Japanese medaka. However, in this study, if we only focused on Vtg gene change in males, E3 had strong estrogenic effects on male medaka under the conditions of these experiments.

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Estriol acts as a GPR30 antagonist in estrogen receptor-negative breast cancer cells

Cited by 110 publications

References 62 publications

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

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

GPCRs and cancer

Long-term exposure investigating the estrogenic potency of estriol in Japanese medaka (Oryzias latipes)

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