Research team

Research objectives

The Molecular Endocrinology Programme (MEP) carries out research on the molecular physiology and pharmacology of steroid receptors with the scope of exploiting their potential in the prognosis and treatment of endocrine-related degenerative diseases. The R&D activities of the Programme are developing in two closely inter-related research directions investigating the role of, 1) estrogen receptor as prognostic marker and therapeutic target and, 2) glucocorticoid receptor as modulator of gene expression under cell stress conditions.  

Fig. 1. Immunostaining of normal (A) and hyperplastic (B) human breast tissue using home made monoclonal antibody B1C1 to estrogen receptor beta (ERβ1) (x400). (Chantzi et al, Insights into ectopic estrogen receptor expression, nucleocytoplasmic distribution and interaction with chromatin obtained with new antibodies to estrogen receptor α and β. Steroids 2011;76:974-85).

Fig. 2. Differential Estrogen Receptor Subtype Modulators: Crystal structure of (A) estradiol-ERα and (B) raloxifene-ERβ complex (red) superimposed to the global minimum structure of compound 8 on ERα and ERβ, respectively, (blue), as obtained using docking calculations. Only the most important amino acid residues of the ER-binding cavity are shown (Alexi et al, Differential estrogen receptor subtype modulators: assessment of estrogen receptor subtype-binding selectivity and transcription-regulating properties of new cycloalkyl pyrazoles. J Steroid Biochem Mol Biol. 2009;117:159-67).

Fig. 3.  Genome-wide profiles of GR and p65 (NF-kB subunit) binding sites and target genes. RNA Pol II (RNAPII) and GR (left panel) or p65 ChIP-seq data (right panel) illustrate RNAPII occupancy and GR and p65 binding in the promoter and/or within the gene body of target genes upon ligand treatment. RNAPII occupancy was used as a direct read-out of transcription of the regulated genes (Rao et al, Co-activation of GR and NFKB alters the repertoire of their binding sites and target genes. Genome Research 2011 Jul 12).

Competitively funded Projects (2006 - ):

Hellenic General Secretariat for Research and Technology:

1. New 09ΣΥΝ-11-1076 (2011-2014): National action 'Cooperation' - Sub-action Ι: Medium & Small Scale Cooperative Projects: "Development of natural products and analogues for osteoporosis prevention: transcriptomic, proteomic and metabolomic approaches". Participants: Department of Pharmacognosy and Natural Products Chemistry-School of Pharmacy-NKUA, Molecular Endocrinology Programme-IBRB-NHRF, Musculoskeletal System Research Lab-School of Medicine-NKUA, Lavipharm SA.

2. New 09ΣΥΝ-11-1076 (2010-2014): National action 'Cooperation' - Sub-action ΙΙ: Large Scale Cooperative Projects: "PIK3CA Oncogenic Mutations in Breast and Colon Cancers: Development of Targeted Anticancer Drugs and Diagnostics". Participants: Genetics Division-BRFAA, Signal-mediated Gene Expression-Molecular Endocrinology-Metabolic Engineering & Bioinformatics Programmes-IBRB-NHRF, BRI-FORTH, ProActina; Pharmathen Pharmaceuticals, Bioiatriki.

3. PENED03-ED644 (2006-09): "In search of a role for estrogen receptor beta in breast cancer". Participants: Molecular Endocrinology Programme-IBRB-NHRF and School of Medicine-Univ. of Athens.

4. 02DSBEPRO32 (2006-07): "Assessment of the estrogenic activity of natural compounds and derivatives thereof: Development of novel neutraceuticals and cosmetics". Participants: Lavipharm SA, Molecular Endocrinology Programme-IBRB-NHRF and School of Pharmacy-Univ. of Athens.

5. Ε!3060-SERMS (2004-07): "Novel Selective Estrogen Receptor Modulators (SERMs): Synthesis and evaluation of biological activities." Participants: ELPEN SA, Molecular Endocrinology Programme-IBRB-NHRF, Dept of Chemistry-Agricultural Univ. of Athens, School of Pharmacy-Univ. of Athens and Molecular Paracitology Division-Heinrich Heine University, Duesseldorf.

6. PENED01-ED258 (2002-06): "Neurosteroids; Investigation of the mechanism of action of neurosteroids as neuroprotective agents; Development of new neurosteroids of high neuroprotective and marginal hormonal activity". Participants: School of Medicine-Univ. of Crete, Molecular Endocrinology Programme-IBRB-NHRF, IOPC-NHRF and GALENICA S.A.

European Union:

7. MEST-CT-2005-020575 (2006-10): ''A European Research Training Site for the Design and Synthesis of Novel Neuroprotective and Hypoglycaemic Agents through a Multi-disciplinary approach''. Coordinator: IOPC-NHRF.

8. FOOD-CT-2005-513943 (2005-10):"ECNIS-Environmental Cancer risks, Nutrition and Individual Susceptibility", Network of Excellence. Coordinator: Dr K Rydzynski. IBRB participants: Chemical Carcinogenesis and Genetic Toxicilogy, Molecular Endocrinology & Enzymology Programmes.

9. MTKD-CT-2004-509836 (2004-08): "Macromolecular assemblies involved in regulated gene expression: Structure/functional characteristics, interplay and novel functions". Coordinator: Dr A Guialis, IBRB-Molecular Biology Programme. Participants: IBRB-Signal Mediated Gene Expression and Molecular Endocrinology Programmes.

10. HPMD-CT-2001-00116 (2002-06): "Regulation of transcription and mRNA processing by oncogenic signals". Coordinator: Dr A. Pintzas, IBRB-Signal-mediated gene expression Programme. Participants: IBRB-Molecular Endocrinology and Molecular Biology Programmes.

Peer-reviewed publications of the Programme† (2006 -  ):

1. Rao NRA, McCalman MT, Moulos P, Francoijs KJ, Chatziioannou A, Kolisis FN, Alexis MN, Mitsiou DJ, Stunnenberg HG. Co-activation of GR and NFKB alters the repertoire of their binding sites and target genes. Genome Research 2011 Jul 12.
   
   
2. Koufaki M, Tsatsaroni A, Alexi X, Guerrand H, Zerva S, Alexis MN. Isoxazole substituted chromans against oxidative stress-induced neuronal damage. Bioorg Med Chem. 2011 Jun 29.
   
   
3. Chantzi NI, Meligova AK, Dhimolea E, Petrou CC, Mitsiou DJ, Pechtelidou A, Florentin I, Kitraki E, Cordopatis P, Tiniakos DG, Alexis MN. Insights into ectopic estrogen receptor expression, nucleocytoplasmic distribution and interaction with chromatin obtained with new antibodies to estrogen receptor α and β. Steroids Sep-Oct;76(10-11):974-85.
   
   
4. Psarra AM, Sekeris CE. Glucocorticoids induce mitochondrial gene transcription in HepG2 cells Role of the mitochondrial glucocorticoid receptor. Biochim Biophys Acta. 2011 Jun 2.
   
   
5. Koukoulitsa C, Durdagi S, Siapi E, Villalonga-Barber C, Alexi X, Steele BR, Micha-Screttas M, Alexis MN, Tsantili-Kakoulidou A, Mavromoustakos T. Comparison of thermal effects of stilbenoid analogs in lipid bilayers using differential scanning calorimetry and molecular dynamics: correlation of thermal effects and topographical position with antioxidant activity. Eur Biophys J. 2011 Jul;40(7):865-75.
   
   
6. Lagiou A, Samoli E, Georgila C, Zourna P, Barbouni A, Vassilarou D, Tsikkinis A, Sekeris CE, Trichopoulos D, Lagiou P. Diet and expression of estrogen alpha and progesterone receptors in malignant mammary tissue. Nutr Cancer. 2011 Jan;63(1):65-72.
   
   
7. Villalonga-Barber C, Meligova AK, Alexi X, Steele BR, Kouzinos CE, Screttas CG, Katsanou ES, Micha-Screttas M, Alexis MN. New hydroxystilbenoid derivatives endowed with neuroprotective activity and devoid of interference with estrogen and aryl hydrocarbon receptor-mediated transcription. Bioorg Med Chem. 2011Jan 1;19(1):339-51.
   
   
8. Koufaki M, Theodorou E, Alexi X, Alexis MN. Synthesis of a second generation chroman/catechol hybrids and evaluation of their activity in protecting neuronal cells from oxidative stress-induced cell death. Bioorg Med Chem. 2010 Jun 1;18(11):3898-909.
   
   
9. Koufaki M, Theodorou E, Alexi X, Nikoloudaki F, Alexis MN. Synthesis of tropolone derivatives and evaluation of their in vitro neuroprotective activity. Eur J Med Chem. 2010 Mar;45(3):1107-12.
   
   
10. Tchokouaha RF, Alexi X, Chosson E, Besson T, Skaltsounis AL, Seguin E, Alexis MN, Wandji J. Erymildbraedin A and B, two novel cytotoxic dimethylpyrano-isoflavones from the stem bark of Erythrina mildbraedii: evaluation of their activity toward endocrine cancer cells. J Enzyme Inhib Med Chem. 2010 Apr;25(2):228-33.
    
    
11. Calogeropoulou T, Avlonitis N, Minas V, Alexi X, Pantzou A, Charalampopoulos I, Zervou M, Vergou V, Katsanou ES, Lazaridis I, Alexis MN, Gravanis A. Novel dehydroepiandrosterone derivatives with antiapoptotic, neuroprotective activity. J Med Chem. 2009 Nov 12;52(21):6569-87.
    
    
12. Alexi X, Kasiotis KM, Fokialakis N, Lambrinidis G, Meligova AK, Mikros E, Haroutounian SA, Alexis MN. Differential estrogen receptor subtype modulators: assessment of estrogen receptor subtype-binding selectivity and transcription-regulating properties of new cycloalkyl pyrazoles. J Steroid Biochem Mol Biol. 2009 Nov;117(4-5):159-67.
    
    
13. Djiogue S, Halabalaki M, Alexi X, Njamen D, Fomum ZT, Alexis MN, Skaltsounis AL. Isoflavonoids from Erythrina poeppigiana: evaluation of their binding affinity for the estrogen receptor. J Nat Prod. 2009 Sep;72(9):1603-7.
    
    
14. Koufaki M, Kiziridi C, Alexi X, Alexis MN. Design and synthesis of novel neuroprotective 1,2-dithiolane/chroman hybrids. Bioorg Med Chem. 2009 Sep 1;17(17):6432-41.
    
    
15. Ioannou E, Abdel-Razik AF, Alexi X, Vagias C, Alexis MN, Roussis V. 9,11-Secosterols with antiproliferative activity from the gorgonian Eunicella cavolini. Bioorg Med Chem. 2009 Jul 1;17(13):4537-41.
    
    
16. Lagiou P, Samoli E, Lagiou A, Georgila C, Zourna P, Barbouni A, Gkiokas G, Vassilarou D, Tsikkinis A, Sfikas C, Sekeris CE, Hsieh CC, Adami HO, Trichopoulos D. Diet and expression of estrogen alpha and progesterone receptors in the normal mammary gland. Cancer Causes Control. 2009 Jul;20(5):601-7.
    
    
17. Psarra AM, Sekeris CE. Glucocorticoid receptors and other nuclear transcription factors in mitochondria and possible functions. Biochim Biophys Acta. 2009 May;1787(5):431-6. Review.
    
    
18. Lagiou P, Georgila C, Samoli E, Lagiou A, Zourna P, Minaki P, Vassilarou D, Papadiamandis I, Sfikas C, Kalapothaki V, Sekeris CE, Trichopoulos D. Estrogen alpha and progesterone receptor expression in the normal mammary epithelium in relation to breast cancer risk. Int J Cancer. 2009 Jan 15;124(2):440-2.
    
    
19. Halabalaki M, Alexi X, Aligiannis N, Alexis MN, Skaltsounis AL. Ebenfurans IV-VIII from Onobrychis ebenoides: Evidence that C-Prenylation is the Key Determinant of the Cytotoxicity of 3-Formyl-2-arylbenzofurans. J Nat Prod. 2008 Nov 6; 71(11):1934-1937.
    
    
20. Psarra AM, Sekeris CE. Steroid and thyroid hormone receptors in mitochondria. IUBMB Life. 2008 Apr;60(4):210-23. Review.
    
    
21. Ioannou E, Abdel-Razik AF, Zervou M, Christofidis D, Alexi X, Vagias C, Alexis MN, Roussis V. 5alpha,8alpha-Epidioxysterols from the gorgonian Eunicella cavolini and the ascidian Trididemnum inarmatum: isolation and evaluation of their antiproliferative activity. Steroids. 2009 Jan;74(1):73-80.
    
    
22. Ioannou E, Abdel-Razik AF, Alexi X, Vagias C, Alexis MN, Roussis V. Pregnanes with antiproliferative activity from the gorgonian Eunicella cavolini. Tetrahedron 2008; 64:11797-11801.
    
    
23. Tenta R, Pitulis N, Tiblalexi D, Consoulas C, Katopodis H, Konstantinidou E, Manoussakis M, Kletsas D, Alexis MN, Poyatzi A, Koutsilieris M. Mechanisms of the action of zoledronic acid on human MG-63 osteosarcoma cells. Horm Metab Res. 2008 Nov;40(11):737-45.
    
    
24. Bakas P, Liapis A, Vlahopoulos S, Giner M, Logotheti S, Creatsas G, Meligova AK, Alexis MN, Zoumpourlis V. Estrogen receptor alpha and beta in uterine fibroids: a basis for altered estrogen responsiveness. Fertil Steril. 2008 Nov;90(5):1878-85.
    
    
25. Psarra AM, Sekeris CE. Nuclear receptors and other nuclear transcription factors in mitochondria: regulatory molecules in a new environment. Biochim Biophys Acta. 2008 Jan;1783(1):1-11.
    
    
26. Koufaki M, Kiziridi C, Nikoloudaki F, Alexis MN. Design and synthesis of 1,2-dithiolane derivatives and evaluation of their neuroprotective activity. Bioorg Med Chem Lett. 2007 Aug 1;17(15):4223-7.
    
    
27. Voutsas IF, Gritzapis AD, Alexis MN, Katsanou ES, Perez S, Baxevanis CN, Papamichail M. A novel quantitative flow cytometric method for measuring glucocorticoid receptor (GR) in cell lines: correlation with the biochemical determination of GR. J Immunol Methods. 2007 Jul 31;324(1-2):110-9.
    
    
28. Skretas G, Meligova AK, Villalonga-Barber C, Mitsiou DJ, Alexis MN, Micha-Screttas M, Steele BR, Screttas CG, Wood DW. Engineered chimeric enzymes as tools for drug discovery: generating reliable bacterial screens for the detection, discovery, and assessment of estrogen receptor modulators. J Am Chem Soc. 2007 Jul 11;129(27):8443-57.
    
    
29. Solakidi S, Psarra AM, Sekeris CE. Differential distribution of glucocorticoid and estrogen receptor isoforms: localization of GRbeta and ERalpha in nucleoli and GRalpha and ERbeta in the mitochondria of human osteosarcoma SaOS-2 and hepatocarcinoma HepG2 cell lines. J Musculoskelet Neuronal Interact. 2007 Jul-Sep;7(3):240-5.
    
    
30. Katsanou ES, Halabalaki M, Aligiannis N, Mitakou S, Skaltsounis AL, Alexi X, Pratsinis H, Alexis MN. Cytotoxic effects of 2-arylbenzofuran phytoestrogens on human cancer cells: modulation by adrenal and gonadal steroids. J Steroid Biochem Mol Biol. 2007 May;104(3-5):228-36.
    
    
31. Lambrinidis G, Halabalaki M, Katsanou ES, Skaltsounis AL, Alexis MN, Mikros E. Environ Chem Lett. 2006; 4:159-174.Review.
    
    
32. Psarra AM, Solakidi S, Sekeris CE. The mitochondrion as a primary site of action of regulatory agents involved in neuroimmunomodulation. Ann N Y Acad Sci. 2006 Nov;1088:12-22. Review.
    
    
33. Apostolopoulos V, Pietersz GA, Tsibanis A, Tsikkinis A, Drakaki H, Loveland BE, Piddlesden SJ, Plebanski M, Pouniotis DS, Alexis MN, McKenzie IF, Vassilaros S. Pilot phase III immunotherapy study in early-stage breast cancer patients using oxidized mannan-MUC1 [ISRCTN71711835]. Breast Cancer Res. 2006;8(3):R27.
    
    
34. Halabalaki M, Alexi X, Aligiannis N, Lambrinidis G, Pratsinis H, Florentin I, Mitakou S, Mikros E, Skaltsounis AL, Alexis MN. Estrogenic activity of isoflavonoids from Onobrychis ebenoides. Planta Med. 2006 May;72(6):488-93.
    
    
35. Kasiotis KM, Mendorou C, Haroutounian SA, Alexis MN. High affinity 17alpha-substituted estradiol derivatives: synthesis and evaluation of estrogen receptor agonist activity. Steroids. 2006 Mar;71(3):249-55.
    
    
36. Psarra AM, Solakidi S, Sekeris CE. The mitochondrion as a primary site of action of steroid and thyroid hormones: presence and action of steroid and thyroid hormone receptors in mitochondria of animal cells. Mol Cell Endocrinol. 2006 Feb 26;246(1-2):21-33. Review.
    
    
37. Roberts ML, Drosopoulos KG, Vasileiou I, Stricker M, Taoufik E, Maercker C, Guialis A, Alexis MN, Pintzas A. Microarray analysis of the differential transformation mediated by Kirsten and Harvey Ras oncogenes in a human colorectal adenocarcinoma cell line. Int J Cancer. 2006 Feb 1;118(3):616-27.
    
    
38. Koufaki M, Theodorou E, Galaris D, Nousis L, Katsanou ES, Alexis MN. Chroman/catechol hybrids: synthesis and evaluation of their activity against oxidative stress induced cellular damage. J Med Chem. 2006 Jan 12;49(1):300-6.
    

† Includes publications by former MEP researcher Professor CE Sekeris (deceased Sept 2009).

Patents

1. Fokialakis N, Aligiannis N, Mitakou S, Skaltsounis AL, Pratsinis H, Alexis MN. Οnobrychis and Genista products for the prevention and treatment of hormone-dependent disorders. Ο.Β.Ι. 1004825
   
   
2. Alexis MN, Dimolea E, Florentin I, Pechtelidou A and Sekeris CE. Monoclonal and polyclonal antibodies to glucococorticoid and estrogen receptors as immunodiagnostics for cancer prognosis. Ο.Β.Ι. 1005417
   
   
3. Micha-Screttas M, Steele BR, Villalonga-Barber C, Alexis MN. New substituted stilbenoid derivatives with meuroprotective activity. O.B.I. 1005435
   
   
4. Alexis MN, Papahatjis D, Sekeris CE, Assimomitis N, Siriani D. Tissue specific antiestrogens selective for estrogen receptor alpha. Ο.Β.Ι. 1005694
   
   
5. Gravanis A, Calogeropouloy T, Kastanas E, Margioris A, Charalambopoulos I, Avlonitis N, Minas V, Alexaki VI, Tsatsanis C, Alexis MN, Remboutsika E, Vergou B, Neophytou C. Neurosteroid compounds. W02008155534 Α2. AE, AG, AL, AM, AO, AT, AU, AZ, BA, BB, BG, BH, BR, BW, BY, BZ, CA, CH, CN, CO, CR, CU, CZ, DE, DK, DM, DO, DZ, EC, FF, EG, ES, FI, GB, GD, GE, GH, GM, GT, HN, HR, HU, ID, IL, IN, IS, JP, KE, KG, KM, KN, KP, KR, KZ, LA, LC, LK, LR, LS, LT, LU, LY, MA, MD, ME, MG, MK, MN, MW, MX, MY, MZ, NA, NG, NI, NO, NZ, OM, PG, PH, PL, PT, RO, RS, RU, SC, SD, SE, SG, SK, SL, SM, SV, SY, TJ, TM, TN, TR, TT, TZ, UA, UG, US, UZ, VC, VN, ZA, ZM, ZW.
   
   
6. Calogeropoulou T, Alexis MN, Koini E, Avlonitis N, Alexi X. 1,4-Benzoxazine Derivatives. O.B.I. O.B.I. 1007084.