PC3, but not DU145, human prostate cancer cells retain the coregulators required for tumor suppressor ability of androgen receptor
PC3, but not DU145, human prostate cancer cells retain the coregulators required for tumor suppressor ability of androgen receptor
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DOI：
10.1002/pros.20483
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发表时间：
2006-09-01
期刊：
影响因子：
2.8
通讯作者：
Isaacs, John T.
中科院分区：
文献类型：
--
作者：
Litvinov, Ivan V.;Antony, Lizamma;Isaacs, John T.
背景雄激素受体（AR）在正常前列腺上皮中作为肿瘤抑制因子发挥作用，抑制这些细胞的持续增殖。AR的这种肿瘤抑制功能在雄激素耗竭非依赖性（ADI）前列腺癌中丧失。在I型ADI癌症中，AR不表达，而在II型ADI癌症中，AR作为癌基因被重新捕获。PC 3和DU 145人前列腺癌细胞系是早期I型ADI前列腺癌的代表。虽然这些细胞不表达AR，但尚不清楚它们是否保留了AR依赖性肿瘤抑制所必需的共激活因子。为了回答这个问题，评估了PC 3和DU 145细胞对AR蛋白表达的反应。为此，将慢病毒AR（Lenti-AR）表达系统工程化以编码AR转录物，所述AR转录物包括含有所有先前鉴定的转录后调控序列的适当的5'和3'非翻译区（UTR）。分别通过Western印迹和荧光素酶测定来评估Lenti-AR转导的细胞中的AR表达和转录活性。在培养物和小鼠异种移植物中的细胞生长与p21、p27和p45 SKP 2蛋白表达变化的相关性进行了评价。Lenti-AR转导的PC 3和DU 145系以适当的生理水平表达转录功能性AR蛋白。AR蛋白在PC 3-Lenti-AR细胞中的表达和参与导致p21的反式激活以及随后这些细胞在培养物和小鼠异种移植物中的生长抑制。这种抑制是由于这些细胞的诱导GI停滞，如通过p27和p45（SKP 2）蛋白的表达变化所记录的。在DU 145-Lenti-AR细胞中未观察到这种生长抑制。这些结果证明，PC 3细胞而不是DU 145细胞保留了AR肿瘤抑制能力所需的辅助调节因子。
BACKGROUND. Androgen receptor (AR) functions in normal prostate epithelium as a tumor suppressor to inhibit continuous proliferation of these cells. Such tumor suppressor function of AR is lost in androgen depletion independent (ADI) prostate cancers. In type-I ADI cancers AR is not expressed, while in type-II ADI cancers AR is recaptured as an oncogene. The PC3 and DU145 human prostate cancer cell lines are representative of the earlier type-I ADI prostate cancers. While these cells do not express AR, it is unclear whether they retained the coactivators necessary for AR-dependent tumor suppression. To answer this question the response to AR protein expression by PC3 and DU145 cells was evaluated.METHODS. To do this, a lentiviral AR (Lenti-AR) expression system was engineered to encode an AR transcript which includes appropriate 5' and 3' untranslated regions (UTRs) containing all previously identified post-transcriptional regulatory sequences. AR expression and transcriptional activity were evaluated in Lenti-AR transduced cells by Western blot and luciferase assay, respectively. Cell growth in culture and in mouse xenografts was evaluated in correlation to expression changes in p21, p27, and p45 SKP2 proteins.RESULTS. Lenti-AR transduced PC3 and DU145 lines expressed transcriptionally functional AR protein at appropriate physiological levels. Expression and engagement of AR protein in PC3-Lenti-AR cells resulted in transactivation of p21 and subsequent growth inhibition of these cells in culture and in mouse xenografts. Such inhibition was due to induced GI arrest of these cells as documented by expression changes in p27 and p45(SKP2) proteins. Such growth inhibition was not observed in DU145-Lenti-AR cells.CONCLUSIONS. These results document that PC3, but not DU145 cells retain the coregulators needed for AR tumor suppressor ability.