Abstract
ABSTRACTEstrogens regulate numerous pathophysiological processes, mainly by binding to and activating estrogen receptor (ER)α and ERβ. Increasing amounts of evidence have recently demonstrated that G-protein coupled receptor 30 (GPR30; also known as GPER) is also involved in diverse biological responses to estrogens both in normal and cancer cells. The classical ER and GPER share several features, including the ability to bind to identical compounds; nevertheless, some ligands exhibit opposed activity through these receptors. It is worth noting that, owing to the availability of selective agonists and antagonists of GPER for research, certain differential roles elicited by GPER compared with ER have been identified. Here, we provide evidence on the molecular mechanisms through which a calixpyrrole derivative acts as a GPER antagonist in different model systems, such as breast tumor cells and cancer-associated fibroblasts (CAFs) obtained from breast cancer patients. Our data might open new perspectives toward the development of a further class of selective GPER ligands in order to better dissect the role exerted by this receptor in different pathophysiological conditions. Moreover, calixpyrrole derivatives could be considered in future anticancer strategies targeting GPER in cancer cells.
Highlights
Breast cancer is the most frequent malignancy in women, and mortality of affected individuals is mainly caused by the development of metastatic processes (Siegel et al, 2012), which is driven at least in part by the tumor microenvironment (Schedin and Borges, 2009)
In accordance with the results obtained in computational studies, the authors established the molecular mechanisms through which a calixpyrrole derivative, named calix[4]pyrrole derivative [meso-octamethylcalix[4]pyrrole (C4PY), might act as a GPER antagonist in breast tumor cells and cancer-associated fibroblasts (CAFs) that were obtained from individuals with breast cancer
This structural characteristic, the dimensions and the conformation adopted meant that C4PY displayed a full interaction with the receptor binding cleft by forming a hydrogen bond with Glu115, different hydrophobic contacts with residues Leu119, Thr201, Phe206, Phe208, Arg299, His302, Pro303 and His307, and involving amino acids belonging to transmembrane helices (TM) II, extracellular loop (EL) 2 and TM VII (Fig. 2)
Summary
Breast cancer is the most frequent malignancy in women, and mortality of affected individuals is mainly caused by the development of metastatic processes (Siegel et al, 2012), which is driven at least in part by the tumor microenvironment (Schedin and Borges, 2009). Cancer cells produce secreted factors that activate fibroblasts into proliferative cells, namely cancer-associated fibroblasts (CAFs), which in turn promote the survival and growth of cancer cells Considering that GPER and ER bind promiscuously to many compounds, including endogenous and environmental estrogens as well as antiestrogens (Lappano et al, 2012a; Prossnitz and Barton, 2011), an ongoing major challenge in dissecting the transduction network mediated by GPER is the discovery of novel agents able to act selectively through this receptor, certain ligands have been identified in our and other previous studies (Bologa et al, 2006; Dennis et al, 2009, 2011; Lappano et al, 2012b; Maggiolini et al, 2015; Sinicropi et al, 2015)
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
