Corbin Joshua M, Georgescu Constantin, Wang Lin, Wren Jonathan D, Bieniasz Magdalena, Xu Chao, Asch Adam S, Ruiz Echevarría Maria J
Stephenson Cancer Center, 800 NE 10th Street, Oklahoma City, OK 73104, USA.
Department of Pathology, Biomedical Sciences Building, University of Oklahoma Health Sciences Center, 940 Stanton L. Young Boulevard, Oklahoma City, OK 73104, USA.
Mol Ther Nucleic Acids. 2023 Jun 28;33:257-272. doi: 10.1016/j.omtn.2023.06.021. eCollection 2023 Sep 12.
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.
阻断雄激素受体信号传导是晚期前列腺癌（PCa）治疗的主要手段。然而，对靶向该信号通路的单一药物产生的获得性耐药会导致致命性去势抵抗性PCa的发展。联合治疗方法是治疗晚期疾病的一种有前景的策略。在此，我们基于短发夹RNA（shRNAs）/小干扰RNA（siRNAs）本质上作为微小RNA（miRNAs）发挥作用的能力，并通过种子序列互补性同时诱导对众多靶点的RNA干扰，探索一种针对PCa的治疗策略。我们构建了一个文库，其中包含具有所有可能种子序列组合的shRNAs，以鉴定那些在PCa细胞中表达时最有效地降低细胞生长和活力的shRNAs。对其中一些RNA干扰序列的验证表明，毒性作用与种子序列与雄激素受体（AR）共调节和必需基因的3'非翻译区（UTR）的互补性有关。事实上，含有已鉴定毒性种子序列的siRNAs的表达导致AR介导的基因表达受到全面抑制，并降低了细胞周期基因的表达。在小鼠中进行测试时，毒性shRNAs也抑制了去势抵抗性PCa，并在已建立的肿瘤中表现出治疗效果。我们的研究结果突出了雄激素信号网络的RNA干扰作为一种有前景的PCa治疗策略。
