An unbiased seed-based RNAi selection screen identifies small RNAs that inhibit androgen signaling and prostate cancer cell growth.
An unbiased seed-based RNAi selection screen identifies small RNAs that inhibit androgen signaling and prostate cancer cell growth.
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基于种子的无偏 RNAi 选择筛选可识别抑制雄激素信号传导和前列腺癌细胞生长的小 RNA。
DOI：
10.1016/j.omtn.2023.06.021
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发表时间：
2023-09-12
期刊：
影响因子：
--
通讯作者：
Echevarria, Maria J. Ruiz
中科院分区：
文献类型：
--
作者：
Corbin, Joshua M.;Georgescu, Constantin;Wang, Lin;Wren, Jonathan D.;Bieniasz, Magdalena;Xu, Chao;Asch, Adam S.;Echevarria, Maria J. Ruiz
Blocking androgen receptor signaling is the mainstay of therapy for advanced prostate cancer (PCa). However, acquired resistance to single agents targeting this pathway results in the development of lethal castration-resistant PCa. Combination therapy approaches represent a promising strategy for the treatment of advanced disease. Here, we explore a therapeutic strategy for PCa based on the ability of shRNAs/siRNAs to function essentially as miRNAs and, via seed sequence complementarity, induce RNA interference of numerous targets simultaneously. We developed a library that contained shRNAs with all possible seed sequence combinations to identify those ones that most potently reduce cell growth and viability when expressed in PCa cells. Validation of some of these RNAi sequences indicated that the toxic effect is associated with seed sequence complementarity to the 3′ UTR of AR coregulatory and essential genes. In fact, expression of siRNAs containing the identified toxic seed sequences led to global inhibition of AR-mediated gene expression and reduced expression of cell-cycle genes. When tested in mice, the toxic shRNAs also inhibited castration-resistant PCa and exhibited therapeutic efficacy in pre-established tumors. Our findings highlight RNAi of androgen signaling networks as a promising therapeutic strategy for PCa. Ruiz Echevarría and colleagues describe a random seed-based RNAi selection screen identifying shRNAs/siRNAs that inhibit PCa cell growth/viability. The toxic shRNAs/siRNAs function as specialized miRNAs to simultaneously target multiple androgen receptor (AR) coregulators, essential for AR signaling and PCa cell survival. This suggests RNAi of hormone signaling networks as therapeutic strategy for PCa.
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影响因子：
5.6
作者：
Bielska A;Skwarska A;Kretowski A;Niemira M
通讯作者：
Niemira M
影响因子：
6.4
作者：
Hagman, Zandra;Larne, Olivia;Ceder, Yvonne
通讯作者：
Ceder, Yvonne
影响因子：
56.9
作者：
Blomen, Vincent A.;Majek, Peter;Brummelkamp, Thijn R.
通讯作者：
Brummelkamp, Thijn R.
DOI：
10.1016/s0140-6736(21)02437-5
发表时间：
2022-01-29
期刊：
Lancet (London, England)
影响因子：
--
作者：
Attard G;Murphy L;Clarke NW;Cross W;Jones RJ;Parker CC;Gillessen S;Cook A;Brawley C;Amos CL;Atako N;Pugh C;Buckner M;Chowdhury S;Malik Z;Russell JM;Gilson C;Rush H;Bowen J;Lydon A;Pedley I;O'Sullivan JM;Birtle A;Gale J;Srihari N;Thomas C;Tanguay J;Wagstaff J;Das P;Gray E;Alzoueb M;Parikh O;Robinson A;Syndikus I;Wylie J;Zarkar A;Thalmann G;de Bono JS;Dearnaley DP;Mason MD;Gilbert D;Langley RE;Millman R;Matheson D;Sydes MR;Brown LC;Parmar MKB;James ND;Systemic Therapy in Advancing or Metastatic Prostate cancer: Evaluation of Drug Efficacy (STAMPEDE) investigators
通讯作者：
Systemic Therapy in Advancing or Metastatic Prostate cancer: Evaluation of Drug Efficacy (STAMPEDE) investigators
DOI：
10.1016/j.omtn.2021.03.002
发表时间：
2021-06-04
期刊：
Molecular therapy. Nucleic acids
影响因子：
--
作者：
Corbin JM;Georgescu C;Wren JD;Xu C;Asch AS;Ruiz-Echevarría MJ
通讯作者：
Ruiz-Echevarría MJ