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Modulators of prostate cancer cell proliferation and viability identified by short-hairpin RNA library screening.

Dahlman KB, Parker JS, Shamu T, Hieronymus H, Chapinski C, Carver B, Chang K, Hannon GJ, Sawyers CL
PLoS One. 2012 7 (4): e34414

PMID: 22509301 · PMCID: PMC3324507 · DOI:10.1371/journal.pone.0034414

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.

MeSH Terms (18)

Androgen Antagonists Anilides Apoptosis Cell Line, Tumor Cell Proliferation Cell Survival Databases, Nucleic Acid Genes, Neoplasm Humans Male Molecular Targeted Therapy Nitriles Prostatic Neoplasms Recurrence Reproducibility of Results RNA, Small Interfering RNA Interference Tosyl Compounds

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