Preclinical studies using cisplatin/carboplatin to restore the Enzalutamide sensitivity via degrading the androgen receptor splicing variant 7 (ARv7) to further suppress Enzalutamide resistant prostate cancer.
Preclinical studies using cisplatin/carboplatin to restore the Enzalutamide sensitivity via degrading the androgen receptor splicing variant 7 (ARv7) to further suppress Enzalutamide resistant prostate cancer.
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DOI：
10.1038/s41419-020-02970-4
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发表时间：
2020-11-02
影响因子：
9
通讯作者：
Chang C
中科院分区：
文献类型：
--
作者：
Chou FJ;Lin C;Tian H;Lin W;You B;Lu J;Sahasrabudhe D;Huang CP;Yang V;Yeh S;Niu Y;Chang C
FDA批准的抗雄激素Enzalutamide（Enzalutamide）已成功用作最后一线治疗，将去势抵抗性前列腺癌（CRPC）患者的生存期延长了4.8个月。然而，CRPC患者最终发展出可能涉及诱导雄激素受体（AR）剪接变体ARv 7的酶耐药性。在这里，我们发现目前用于化学疗法/放射疗法以抑制肿瘤进展的顺铂（Cis）或卡铂可以通过直接降解/抑制ARv 7来恢复多种Enz-resistant（EnzR）CRPC细胞中的Enz-sensitivity。将顺式或卡铂与Enz疗法组合也可以延迟CRPC C4-2细胞中的Enz-resistance的发展。机制分析发现，顺铂或卡铂可能通过多种机制降低ARv 7的表达，包括靶向lncRNA-Malat 1/SF 2 RNA剪接复合物和通过改变泛素化增加ARv 7的降解。使用植入EnzR 1-C4-2细胞的体内小鼠模型的临床前研究也证明，Cis + Enz治疗比单独Enz治疗更好地抑制了EnzR CRPC进展。这些结果不仅揭示了以前未被认识到的Cis通过靶向Malat 1/SF 2复合物和泛素化信号降解ARv 7的机制，还可能在不久的将来提供一种新的现成疗法来进一步抑制EnzR CRPC进展。
The FDA-approved anti-androgen Enzalutamide (Enz) has been used successfully as the last line therapy to extend castration-resistant prostate cancer (CRPC) patients’ survival by an extra 4.8 months. However, CRPC patients eventually develop Enz-resistance that may involve the induction of the androgen receptor (AR) splicing variant ARv7. Here we found that Cisplatin (Cis) or Carboplatin, currently used in chemotherapy/radiation therapy to suppress tumor progression, could restore the Enz sensitivity in multiple Enz-resistant (EnzR) CRPC cells via directly degrading/suppressing the ARv7. Combining Cis or Carboplatin with Enz therapy can also delay the development of Enz-resistance in CRPC C4-2 cells. Mechanism dissection found that Cis or Carboplatin might decrease the ARv7 expression via multiple mechanisms including targeting the lncRNA-Malat1/SF2 RNA splicing complex and increasing ARv7 degradation via altering ubiquitination. Preclinical studies using in vivo mouse model with implanted EnzR1-C4-2 cells also demonstrated that Cis plus Enz therapy resulted in better suppression of EnzR CRPC progression than Enz treatment alone. These results not only unveil the previously unrecognized Cis mechanism to degrade ARv7 via targeting the Malat1/SF2 complex and ubiquitination signals, it may also provide a novel and ready therapy to further suppress the EnzR CRPC progression in the near future.
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影响因子：
7.7
作者：
Balbas MD;Evans MJ;Hosfield DJ;Wongvipat J;Arora VK;Watson PA;Chen Y;Greene GL;Shen Y;Sawyers CL
通讯作者：
Sawyers CL
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：
9
作者：
通讯作者：
--
影响因子：
3
作者：
Buonerba, Carlo;Federico, Piera;Lorenzo, Giuseppe Di
通讯作者：
Lorenzo, Giuseppe Di
影响因子：
28.2
作者：
Korpal, Manav;Korn, Joshua M.;Zhu, Ping
通讯作者：
Zhu, Ping