Selective inhibition of human 3β-hydroxysteroid dehydrogenase type 1 as a potential treatment for breast cancer.
Selective inhibition of human 3β-hydroxysteroid dehydrogenase type 1 as a potential treatment for breast cancer.
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DOI：
10.1016/j.jsbmb.2010.08.003
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发表时间：
2011-05
影响因子：
4.1
通讯作者：
Kacsoh, Balint
中科院分区：
文献类型：
--
作者：
Thomas, James L.;Bucholtz, Kevin M.;Kacsoh, Balint
关键词：
Human 3β-hydroxysteroid dehydrogenase/isomerase type 1 (3β-HSD1) is a critical enzyme in the conversion of DHEA to estradiol in breast tumors and may be a target enzyme for inhibition in the treatment of breast cancer in postmenopausal women. Human 3β-HSD2 participates in the production of cortisol and aldosterone in the human adrenal gland in this population. In our recombinant human breast tumor MCF-7 Tet-off cells that express either 3β-HSD1 or 3β-HSD2, trilostane and epostane inhibit the DHEA-induced proliferation of MCF-7 3β-HSD1 cells with 12-to 16- fold lower IC50 values compared to the MCF-7 3β-HSD2 cells. Trilostane and epostane also competitively inhibit purified human 3β-HSD1 with 12-fold to 16-fold lower Ki values compared to the noncompetitive Ki values measured for human 3β-HSD2. Using our structural model of 3β-HSD1, trilostane was docked in the active site of 3β-HSD1, and Arg195 in 3β-HSD1 or Pro195 in 3β-HSD2 was identified as a potentially critical residue. The R195P-1 mutant of 3β-HSD1 and the P195R-2 mutant of 3β-HSD2 were created, expressed and purified. Kinetic analyses of enzyme inhibition suggest that the high-affinity, competitive inhibition of 3β-HSD1 by trilostane may be related to the presence of Arg195 in 3β-HSD1 vs Pro195 in 3β-HSD2. In addition, His156 in 3β-HSD1 may play a role in the higher affinity of 3β-HSD1 for substrates and inhibitors compared to 3β-HSD2 containing Try156. Structural modeling of the 3β-HSD1 dimer identified a possible interaction between His156 on one subunit and Gln105 on the other. Kinetic analyses of the H156Y-1, Q105M-1 and Q105M-2 support subunit interactions that contribute to the higher affinity of 3β-HSD1 for the inhibitor, epostane, compared to 3β-HSD2.
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影响因子：
5.1
作者：
Persson, Bengt;Kallberg, Yvonne;Bray, James E.;Bruford, Elspeth;Dellaporta, Stephen L.;Favia, Angelo D.;Gonzalez Duarte, Roser;Jornvall, Hans;Kavanagh, Kathryn L.;Kedishvili, Natalia;Kisiela, Michael;Maserk, Edmund;Mindnich, Rebekka;Orchard, Sandra;Penning, Trevor M.;Thornton, Janet M.;Adamski, Jerzy;Oppermann, Udo
通讯作者：
Oppermann, Udo
影响因子：
4.1
作者：
Penning, TM;Burczynski, ME;Ratnam, K
通讯作者：
Ratnam, K
DOI：
10.1016/j.jsbmb.2005.01.011
发表时间：
2005-02-01
影响因子：
4.1
作者：
Samson, M;Labrie, F;Luu-The, V
通讯作者：
Luu-The, V
影响因子：
--
作者：
Gingras, S;Moriggl, R;Simard, J
通讯作者：
Simard, J
DOI：
10.1016/s0960-0760(00)00077-7
发表时间：
2000-07-01
影响因子：
4.1
作者：
Billich, A;Nussbaumer, P;Lehr, P
通讯作者：
Lehr, P