An unbiased seed-based RNAi selection screen identifies small RNAs that inhibit androgen signaling and prostate cancer cell growth
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 th...
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| Format: | Article |
| Language: | English |
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Elsevier
2023-09-01
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| Series: | Molecular Therapy: Nucleic Acids |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2162253123001713 |
| _version_ | 1797776644121821184 |
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| author | Joshua M. Corbin Constantin Georgescu Lin Wang Jonathan D. Wren Magdalena Bieniasz Chao Xu Adam S. Asch Maria J. Ruiz Echevarría |
| author_facet | Joshua M. Corbin Constantin Georgescu Lin Wang Jonathan D. Wren Magdalena Bieniasz Chao Xu Adam S. Asch Maria J. Ruiz Echevarría |
| author_sort | Joshua M. Corbin |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-03-12T22:52:51Z |
| format | Article |
| id | doaj.art-41fabf28d4364d8697b56a2f8a9cd7e7 |
| institution | Directory Open Access Journal |
| issn | 2162-2531 |
| language | English |
| last_indexed | 2024-03-12T22:52:51Z |
| publishDate | 2023-09-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Molecular Therapy: Nucleic Acids |
| spelling | doaj.art-41fabf28d4364d8697b56a2f8a9cd7e72023-07-20T04:38:18ZengElsevierMolecular Therapy: Nucleic Acids2162-25312023-09-0133257272An unbiased seed-based RNAi selection screen identifies small RNAs that inhibit androgen signaling and prostate cancer cell growthJoshua M. Corbin0Constantin Georgescu1Lin Wang2Jonathan D. Wren3Magdalena Bieniasz4Chao Xu5Adam S. Asch6Maria J. Ruiz Echevarría7Stephenson 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; Corresponding author: Joshua M. Corbin, Stephenson Cancer Center, 800 NE 10th Street, Oklahoma City, OK 73104, USA.Genes and Human Disease Research Program, Division of Genomics and Data Sciences, Oklahoma Medical Research Foundation, 825 NE 13th Street, Oklahoma City, OK 73104, USAAging and Metabolism Program, Oklahoma Medical Research Foundation, 825 NE 13th Street, Oklahoma City, OK 73104, USAGenes and Human Disease Research Program, Division of Genomics and Data Sciences, Oklahoma Medical Research Foundation, 825 NE 13th Street, Oklahoma City, OK 73104, USAAging and Metabolism Program, Oklahoma Medical Research Foundation, 825 NE 13th Street, Oklahoma City, OK 73104, USAStephenson Cancer Center, 800 NE 10th Street, Oklahoma City, OK 73104, USA; Department of Biostatistics and Epidemiology, Hudson College of Public Health, University of Oklahoma Health Sciences Center, 801 N.E. 13 Street, Oklahoma City, OK 73104, USAStephenson Cancer Center, 800 NE 10th Street, Oklahoma City, OK 73104, USA; Department of Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USAStephenson 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; Department of Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA; Corresponding author: Maria J. Ruiz Echevarría, Stephenson Cancer Center, 800 NE 10th Street, Oklahoma City, OK 73104, USA.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.http://www.sciencedirect.com/science/article/pii/S2162253123001713MT: Oligonucleotides: Therapies and Applicationsprostate cancerRNA interferencesmall RNAseed sequenceandrogen signaling |
| spellingShingle | Joshua M. Corbin Constantin Georgescu Lin Wang Jonathan D. Wren Magdalena Bieniasz Chao Xu Adam S. Asch Maria J. Ruiz Echevarría An unbiased seed-based RNAi selection screen identifies small RNAs that inhibit androgen signaling and prostate cancer cell growth Molecular Therapy: Nucleic Acids MT: Oligonucleotides: Therapies and Applications prostate cancer RNA interference small RNA seed sequence androgen signaling |
| title | An unbiased seed-based RNAi selection screen identifies small RNAs that inhibit androgen signaling and prostate cancer cell growth |
| title_full | An unbiased seed-based RNAi selection screen identifies small RNAs that inhibit androgen signaling and prostate cancer cell growth |
| title_fullStr | An unbiased seed-based RNAi selection screen identifies small RNAs that inhibit androgen signaling and prostate cancer cell growth |
| title_full_unstemmed | An unbiased seed-based RNAi selection screen identifies small RNAs that inhibit androgen signaling and prostate cancer cell growth |
| title_short | An unbiased seed-based RNAi selection screen identifies small RNAs that inhibit androgen signaling and prostate cancer cell growth |
| title_sort | unbiased seed based rnai selection screen identifies small rnas that inhibit androgen signaling and prostate cancer cell growth |
| topic | MT: Oligonucleotides: Therapies and Applications prostate cancer RNA interference small RNA seed sequence androgen signaling |
| url | http://www.sciencedirect.com/science/article/pii/S2162253123001713 |
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