摘要
前列腺癌发病率在男性所有恶性肿瘤中位居第二[1]。雄激素受体(Androgen receptor,AR)是治疗前列腺癌的重要靶标[2],使用雄激素受体拮抗剂阻断雄激素与AR的结合能够达到治疗目的。常用的雄激素受体拮抗剂有比卡鲁胺(R-bicalutamide)和恩杂鲁胺(Enzalutamide)等,但在使用数月后它们常产生耐药性[3,4]。AR突变是产生耐药性的主要原因[5]。从去势抵抗性前列腺患者的组织样本中发现了一系列氨基酸突变的AR,如:L701H,W741C,W741L,H874Y,F876L,T877A和M895T,这些突变都位于AR的配体结合域(Ligand-Binding Domain,LBD)。我们通过分子模拟和自由能计算,从分子水平上阐明耐药机制。结果表明,AR中的螺旋12(H12,像一个盖子位于LBD顶部)在耐药机制中起着关键作用。当R-bicalutamide的B环或enzalutamide的C环靠近H12时,可阻止H12闭合并扭曲了共激活剂结合位点,从而导致无效的转录。相反,当B或C环靠近H11或Loop11-12,有利于H12闭合形成共激活剂结合位点。模拟结果显示,对于R-bicalutamide,W741C/L,W741C_T877A,H874Y突变能使R-bicalutamide产生耐药性,而T877A,F876L,F876L_T877A,L701H,M895T突变不能。对于Enzalutamdie,F876L,F876L_T877A,H874Y,L701H突变能使enzalutamide产生耐药性,而T877A,W741C/L,W741C_T877A,M895T突变不能。
The androgen receptor(AR) is a target for the treatment of prostate cancer.R-bicalutamide and enzalutamide are two commonly used antiandrogens,but prostate tumor will lose their sensitivity to antiandrogen after several months treatment.AR mutation is a vital reason for the drug resistance.Some AR mutations,L701 H,W741C/L,H874 Y,F876L,T877 A and M895 T,were identified from tissue specimens of patients.Molecular dynamics simulation together with energy calculations were used to study the resistance mechanisms.The results indicate that helix H12,which lies on the top of the ligand-binding domain like a cover,plays a vital role for the function of antiandrogen.When the B-ring of R-bicalutamide or C-ring of enzaluamide locates near to H12,which could prevent H12 from closing and distort the coactivator binding site,resulting in the invalid transcription.However,if they are near to H11,H12 tends to close to form a coactivator binding site to facilitate transcription.
引文
[1]Center,M.M.;Jemal,A.;Lortet-Tieulent,J.;Ward,E.Europ.urol,2012,61:1079.
[2]Balk,S.P.Urology,2002,60:132.
[3]Sander,M.D.World J.Urol.2012,30:311.
[4]Dalesio,O.;van Tinteren,H.;Clerke,M.;Peto,R.Lancet.2000,355:1491.
[5]Taplin,M.E.;Bubley,G.J.;Shuster,T.D.;Frantz,M.E.N.Engl.J.Med.1995,332,1393.