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Identifier 000441013
Title Ανεύρεση και μελέτη του μηχανισμού δράσης νέων μικρομοριακών ουσιών που δεσμεύονται στο μεμβρανικό υποδοχέα των ανδρογόνων OXER1
Alternative Title Identification of new micromolecular ligands for the membrane receptor of androgens OXERI1 and study of their mechanism of action
Author Παναγιωτόπουλος, Αθανάσιος Α.
Thesis advisor Καμπά, Μαρία-Ελένη
Reviewer Καστανάς, Ηλίας
Σκαλτσούνης, Αλέξιος-Λέανδρος
Θεοδωρόπουλος, Παναγιώτης
Παναγιωτίδης, Χρήστος
Πυρίντσος, Στέργιος
Νότας, Γεώργιος
Βενυχάκη, Μαρία
Abstract The action of androgens is mediated mainly through intracellular androgen receptors, which belong to the nuclear family of receptors. These receptors are a set of transcription factors that determine key cell processes. A recent study by our team identified an alternative androgen receptor on the membrane of prostate cancer cells, OXER1 (5-oxo-6E, 8Z, 11Z, 14Z-eicosatetraenoic acid receptor). It is a receptor belonging to the GPCRs family, which was isolated and characterized approximately 18 years ago. Prostate cancer is known to be one of the most serious hormone- dependent and hormone-sensitive tumors. Prostate cancer located in the male reproductive system and most types of this cancer develop slowly. Prostate cancer is also very metastatic and can spread to other parts of the body. Epidemiological data on prostate cancer show that it is the second most common cancer. Current treatments for this cancer are not fully effective. Natural products may have a pharmacological effect and a therapeutic benefit in the treatment of diseases such as prostate cancer. Compounds from nature can often be used as a starting point in the process of discovering new drugs. Many prostate cancer therapies aim to inhibit androgen receptor signaling because the role of these receptors in prostate cancer is extremely important. Also, the arachidonic acid signaling pathway plays a key role in carcinogenesis and for this reason many natural products have been tested as inhibitors in the signaling and metabolism pathways of arachidonic acid and its derivatives. Membrane androgen receptors (mARs) are involved in the activation of various kinases and lead to processes that affect the growth and metastasis of cancer cells. Finding natural products as regulators of the action of membrane androgen receptors may be the key to inhibit carcinogenic processes. The research needs for a better understanding of the mechanism of action of androgens and finding new anti-cancer therapeutic targets and / or substances is extremely high. The aim of the dissertation was to identify micromolecular compounds that will bind to the membrane receptor of androgens, OXER1 and will have a competitive effect such as testosterone, since this receptor induces the survival of cancer cells, and possibly explore them as anticancer agents. In particular, OXER1 receptor is an oxo-lipid receptor that defines important functions in conditions such as inflammatory reactions and cancer. Our research team has shown that the OXER1 receptor mediates the rapid effects of androgens, as testosterone binds to it and competes with the actions of its lipid ligand (5-oxo-ETE). The OXER1 receptor is involved in allergic responses that include eosinophils and basophils. In particular, it mediates the effects of 5-oxo- ETE on eosinophil chemotaxis, actin polymerization and L-selectin elimination. It is also involved in the proliferation and development of prostate, breast, kidney and ovarian cancers. OXER1 receptor function has been linked to the inhibition of cyclic 3', 5'-adenosine monophosphoric acid (cAMP), because it binds to a Gαi protein, while at the same time leading to an increase in intracellular calcium. In addition, activation of the OXER1 receptor induces phosphorylation of various kinases such as PI3K, Akt and ERK1/2. To achieve this study, the following approach was followed, starting with the modeling of the interaction of OXER1 receptor with testosterone and 5- oxo-ETE. Due to the large number of natural products studied, an algorithm was designed and developed, allowing the fast and accurate classification of the examined chemical molecules. Next, using the advanced bioinformatics tool, OXER1 competitors were identified. The tool was also used to study the interaction of other receptors / proteins. The selected molecules were analyzed by a wide range of bioinformatics tools. In vitro verification of the competitive properties of the selected compounds was performed in different cellular activities. The identified natural compounds, through bioinformatics methods, were tested in a number of cellular activities, related to the Gα and Gβγ activities of OXER1, such as cAMP, actin polymerization and their effect on calcium ion flow. In conclusion, the achievements of present thesis work are: First, a bioinformatic tool for the fast and accurate testing of different chemical compounds for their ability to act via OXER1. A tool that can be also used to study the interaction of other receptors / proteins (we present three different applications that verify its usefulness). Second, nine compounds as antagonists of OXER1 with the best one verified in vitro, and finally more data on the signaling pathways triggered by testosterone via OXER1. All these support testosterone actions at the membrane level, via OXER1, and provide new tools and agents for possible novel therapeutic approaches in cancer
Language English, Greek
Subject Androgen receptor
Prostate cancer
Ανδρογονικός υποδοχέας
Καρκίνος του προστάτη
Φυσικά προϊόντα
Issue date 2021-07-30
Collection   School/Department--School of Medicine--Department of Medicine--Doctoral theses
  Type of Work--Doctoral theses
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