title: Modulators of prostate cancer cell proliferation and viability identified by short-hairpin RNA library screening.
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.
authors.affiliation: Human Oncology and Pathogenesis Program, Sloan-Kettering Cancer Center, New York, New York, United States of America.
authors.forename: Kimberly Brown
authors.initials: KB
authors.lastname: Dahlman
authors.forename: Joel S
authors.initials: JS
authors.lastname: Parker
authors.forename: Tambudzai
authors.initials: T
authors.lastname: Shamu
authors.forename: Haley
authors.initials: H
authors.lastname: Hieronymus
authors.forename: Caren
authors.initials: C
authors.lastname: Chapinski
authors.forename: Brett
authors.initials: B
authors.lastname: Carver
authors.forename: Kenneth
authors.initials: K
authors.lastname: Chang
authors.forename: Gregory J
authors.initials: GJ
authors.lastname: Hannon
authors.forename: Charles L
authors.initials: CL
authors.lastname: Sawyers
mesh_terms: D000726:Androgen Antagonists / Q000494:pharmacology; D000813:Anilides / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects / Q000235:genetics; D030561:Databases, Nucleic Acid; D052138:Genes, Neoplasm / Q000235:genetics; D006801:Humans; D008297:Male; D058990:Molecular Targeted Therapy; D009570:Nitriles / Q000494:pharmacology; D011471:Prostatic Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism / Q000473:pathology*; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000235:genetics*; D012008:Recurrence; D015203:Reproducibility of Results; D014105:Tosyl Compounds / Q000494:pharmacology
chemical_list: D000726:Androgen Antagonists; D000813:Anilides; D009570:Nitriles; D034741:RNA, Small Interfering; D014105:Tosyl Compounds; C053541:bicalutamide