Proteostasis by STUB1/HSP70 complex controls sensitivity to androgen receptor targeted therapy in advanced prostate cancer.
Proteostasis by STUB1/HSP70 complex controls sensitivity to androgen receptor targeted therapy in advanced prostate cancer.
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DOI：
10.1038/s41467-018-07178-x
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发表时间：
2018-11-16
影响因子：
16.6
通讯作者：
Gao AC
中科院分区：
文献类型：
--
作者：
Liu C;Lou W;Yang JC;Liu L;Armstrong CM;Lombard AP;Zhao R;Noel ODV;Tepper CG;Chen HW;Dall'Era M;Evans CP;Gao AC
蛋白质稳态是癌细胞存活和耐药的潜在机制。成分活性雄激素受体(AR)变异体在晚期前列腺癌中提供抗雄激素抵抗。然而，蛋白平衡在下一代抗雄激素抵抗中的作用以及AR变异的调节机制尚不清楚。在这里，我们显示泛素蛋白酶体系统(UPS)在对苯扎鲁胺/阿比特龙耐药的前列腺癌中被抑制。AR/AR-V7蛋白平衡需要E3泛素连接酶STUB1和HSP70复合体的相互作用。STUB1使AR/AR-V7与HSP70解离，导致AR/AR-V7泛素化和降解。抑制HSP70显著抑制前列腺癌的生长，并通过抑制AR/AR-V7改善苯扎鲁胺/阿比特龙的治疗。在临床上，HSP70在高Gleason评分的前列腺癌中表达上调，并与AR/AR-V7水平相关。我们的结果揭示了一种通过改变UPS来对抗雄激素抵抗的新机制，该机制可能通过抑制HSP70来减少AR-V7的表达，从而克服对AR靶向治疗的抵抗。AR-V7亚型与前列腺癌的抗雄激素耐药相关。在这里，作者表明，AR-V7蛋白的稳定性是由HSP70/STUB1复合体介导的蛋白平衡调节的，这种蛋白平衡导致晚期前列腺癌的耐药性。抑制HSP70使耐药细胞对苯扎鲁胺治疗重新敏感。
Protein homeostasis (proteostasis) is a potential mechanism that contributes to cancer cell survival and drug resistance. Constitutively active androgen receptor (AR) variants confer anti-androgen resistance in advanced prostate cancer. However, the role of proteostasis involved in next generation anti-androgen resistance and the mechanisms of AR variant regulation are poorly defined. Here we show that the ubiquitin-proteasome-system (UPS) is suppressed in enzalutamide/abiraterone resistant prostate cancer. AR/AR-V7 proteostasis requires the interaction of E3 ubiquitin ligase STUB1 and HSP70 complex. STUB1 disassociates AR/AR-V7 from HSP70, leading to AR/AR-V7 ubiquitination and degradation. Inhibition of HSP70 significantly inhibits prostate tumor growth and improves enzalutamide/abiraterone treatments through AR/AR-V7 suppression. Clinically, HSP70 expression is upregulated and correlated with AR/AR-V7 levels in high Gleason score prostate tumors. Our results reveal a novel mechanism of anti-androgen resistance via UPS alteration which could be targeted through inhibition of HSP70 to reduce AR-V7 expression and overcome resistance to AR-targeted therapies. The AR-V7 isoform is associated with anti-androgen drug resistance in prostate cancer. Here, the authors show that AR-V7 protein stability is regulated by HSP70/STUB1 complex-mediated proteostasis which confers drug resistance in late stage prostate cancer. Inhibition of HSP70 re-sensitizes resistant cells to enzalutamide therapy.
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影响因子：
4.8
作者：
He, B;Bai, SX;Wilson, EM
通讯作者：
Wilson, EM
DOI：
10.1158/1078-0432.ccr-17-0017
发表时间：
2017-08-15
期刊：
Clinical cancer research : an official journal of the American Association for Cancer Research
影响因子：
--
作者：
Kohli M;Ho Y;Hillman DW;Van Etten JL;Henzler C;Yang R;Sperger JM;Li Y;Tseng E;Hon T;Clark T;Tan W;Carlson RE;Wang L;Sicotte H;Thai H;Jimenez R;Huang H;Vedell PT;Eckloff BW;Quevedo JF;Pitot HC;Costello BA;Jen J;Wieben ED;Silverstein KAT;Lang JM;Wang L;Dehm SM
通讯作者：
Dehm SM
影响因子：
--
作者：
Kregel S;Chen JL;Tom W;Krishnan V;Kach J;Brechka H;Fessenden TB;Isikbay M;Paner GP;Szmulewitz RZ;Vander Griend DJ
通讯作者：
Vander Griend DJ
DOI：
10.1046/j.1440-1746.2003.03011.x
发表时间：
2003-06-01
影响因子：
4.1
作者：
Hwang, TS;Han, HS;Park, YM
通讯作者：
Park, YM
影响因子：
21.3
作者：
Connell, P;Ballinger, CA;Patterson, C
通讯作者：
Patterson, C