Human Oncology and Pathogenesis Program, Sloan-Kettering Cancer Center, New York, New York, United States of America.
PLoS One. 2012;7(4):e34414. doi: 10.1371/journal.pone.0034414. Epub 2012 Apr 11.
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.
因为当前的激素疗法最终会失效，导致一种被称为去势抵抗性前列腺癌的耐药性和致命性疾病，所以非常有必要确定新的前列腺癌药物靶点。为了从功能上鉴定出那些在与抗雄激素联合使用时沉默可降低前列腺癌细胞增殖或诱导细胞死亡的基因，我们在 LNCaP 人前列腺癌细胞中使用了基于 RNA 干扰的短发夹 RNA 条形码筛选。我们鉴定并验证了四个候选基因（AKT1、PSMC1、STRADA 和 TTK），当在雄激素受体阳性前列腺癌细胞中沉默时，这些基因会损害细胞生长，并增强抗雄激素的增殖抑制作用。用药理学抑制剂抑制 AKT 与抗雄激素联合使用时也会诱导细胞凋亡，这与最近关于前列腺癌细胞中 PI3K 和 AR 通路交叉的证据一致。针对已知前列腺癌途径的发夹的恢复验证了 shRNA 文库筛选在前列腺癌中的广泛应用，是一种确定新候选药物靶点的广泛策略。
