Dahlman, K. B., Parker, J. S., Shamu, T., Hieronymus, H., Chapinski, C., Carver, B., Chang, K., Hannon, G. J., Sawyers, C. L. (2012) Modulators of prostate cancer cell proliferation and viability identified by short-hairpin RNA library screening. PLoS One, 7 (4). ISSN 19326203 (ISSN)
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Abstract
There is significant need to identify novel prostate cancer drug targets because current hormone therapies eventually fail, leading to a drug-resistant and fatal disease termed castration-resistant prostate cancer. To functionally identify genes that, when silenced, decrease prostate cancer cell proliferation or induce cell death in combination with antiandrogens, we employed an RNA interference-based short hairpin RNA barcode screen in LNCaP human prostate cancer cells. We identified and validated four candidate genes (AKT1, PSMC1, STRADA, and TTK) that impaired growth when silenced in androgen receptor positive prostate cancer cells and enhanced the antiproliferative effects of antiandrogens. Inhibition of AKT with a pharmacologic inhibitor also induced apoptosis when combined with antiandrogens, consistent with recent evidence for PI3K and AR pathway crosstalk in prostate cancer cells. Recovery of hairpins targeting a known prostate cancer pathway validates the utility of shRNA library screening in prostate cancer as a broad strategy to identify new candidate drug targets. © 2012 Dahlman et al.
| Item Type: | Paper |
|---|---|
| Uncontrolled Keywords: | AKT1 protein androgen receptor protein PSMC1 protein short hairpin RNA STRADA protein TIK protein unclassified drug anilide antiandrogen bicalutamide nitrile small interfering RNA toluenesulfonic acid derivative AKT1 gene apoptosis article cancer cell cell death cell proliferation controlled study gene genetic identification human human cell microarray analysis prostate cancer PSMC1 gene RNA interference STRADA gene TIK gene validity cell survival drug effect genetics male metabolism molecularly targeted therapy nucleic acid database pathology prostate tumor recurrent disease reproducibility tumor cell line tumor gene Androgen Antagonists Anilides Cell Line, Tumor Databases, Nucleic Acid Genes, Neoplasm Humans Molecular Targeted Therapy Nitriles Prostatic Neoplasms Recurrence Reproducibility of Results RNA, Small Interfering Tosyl Compounds |
| Subjects: | diseases & disorders > cancer bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification diseases & disorders diseases & disorders > cancer > cancer types > prostate cancer bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification > shRNA diseases & disorders > cancer > cancer types |
| CSHL Authors: | |
| Communities: | CSHL Cancer Center Program > Cancer Genetics CSHL Cancer Center Shared Resources > Bioinformatics Service CSHL Cancer Center Shared Resources > DNA Sequencing Service CSHL labs > Hannon lab CSHL Cancer Center Shared Resources > Functional Genomics and Genetics Service |
| Depositing User: | Matt Covey |
| Date: | 2012 |
| Date Deposited: | 09 Jan 2013 16:40 |
| Last Modified: | 30 Oct 2015 16:21 |
| PMCID: | PMC3324507 |
| Related URLs: | |
| URI: | https://repository.cshl.edu/id/eprint/26420 |
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