Personne :
Lin, Sheng-Xiang

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Projets de recherche
Structures organisationnelles
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Université Laval. Département de médecine moléculaire
Identifiant Canadiana

Résultats de recherche

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  • Publication
    Synergistic control of sex hormones by 17b-HSD type 7 : a novel target for estrogen-dependent breast cancer
    (Oxford University Press, 2015-05-12) Poirier, Donald; Wang, Xiao Qiang; Gérard, Catherine; Lin, Sheng-Xiang; Doillon, Charles; Thériault, Jean-François
    17b-hydroxysteroid dehydrogenase (17b-HSD) type 1 is known as a critical target to block the final step of estrogen production in estrogen-dependent breast cancer. Recent confirmation of the role of dyhydroxytestosterone (DHT) in counteracting estrogen induced cell growth prompted us to study the reductive 17b-HSD type 7 (17b-HSD7), which activates estrone while markedly inactivating DHT. The role of DHTin breast cancer cell proliferationis demonstrated by its independent suppression of cell growth in the presence of a physiological concentration of estradiol (E2). Moreover, an integral analysis of a large number of clinical samples in Oncomine datasets demonstrated the overexpression of 17b-HSD7 in breast carcinoma. Inhibition of 17b-HSD7 in breast cancer cells resulted in a lower level of E2 and a higher level of DHT, successively induced regulation of cyclinD1, p21, Bcl-2, and Bik, consequently arrested cell cycle in the G0/G1 phase, and triggered apoptosis and auto-downregulation feedback of the enzyme. Such inhibition led to significant shrinkage of xenograft tumors with decreased cancer cell density and reduced 17b-HSD7 expression. Decreased plasma E2 and elevated plasma DHT levels were also found. Thus, the dual functional 17b-HSD7 is proposed as a novel target for estrogen-dependent breast cancer by regulating the balance of E2 and DHT. This demonstrates a conceptual advance on the general belief that the major role of this enzyme is in cholesterol metabolism.
  • Publication
    Impact of structural modifications at positions 13, 16 and 17 of 16 b -( m -carbamoylbenzyl)-estradiol on 17 b -hydroxysteroid dehydrogenase type 1 inhibition and estrogenic activity
    (Pergamon, 2015-10-28) Barbeau, Xavier; Poirier, Donald; Maltais, René.; Lin, Sheng-Xiang; Lagüe, Patrick; Thériault, Jean-François; Trottier, Alexandre; Perreault, Martin
    The chemical synthesis of four stereoisomers (compounds 5a–d) of 16ß-(m-carbamoylbenzyl)-estradiol, a potent reversible inhibitor of 17ß-hydroxysteroid dehydrogenase type 1 (17ß-HSD1), and two intermediates (compounds 3a and b) was performed. Assignment of all nuclear magnetic resonance signals confirmed the stereochemistry at positions 13, 16 and 17. Nuclear overhauser effects showed clear correlations supporting a C-ring chair conformation for 5a and b and a C-ring boat conformation for 5c and d. These compounds were tested as 17ß-HSD1 inhibitors and to assess their proliferative activity on estrogen-sensitive breast cancer cells (T-47D) and androgen-sensitive prostate cancer cells (LAPC-4). Steroid derivative 5a showed the best inhibitory activity for the transformation of estrone to estradiol (95, 82 and 27%, at 10, 1 and 0.1 µM, respectively), but like the other isomers 5c and d, it was found to be estrogenic. The intermediate 3a, however, was weakly estrogenic at 1 µM, not at all at 0.1 µM, and showed an interesting inhibitory potency on 17ß-HSD1 (90, 59 and 22%, at 10, 1 and 0.1 µM, respectively). As expected, no compound showed an androgenic activity. The binding modes for compounds 3a and b, 5a–d and CC-156 were evaluated from molecular modeling. While the non-polar interactions were conserved for all the inhibitors in their binding to 17ß-HSD1, differences in polar interactions and in binding conformational energies correlated to the inhibitory potencies.