Zolochevska Olga, Figueiredo Marxa L
Department of Comparative Biomedical Sciences, School of Veterinary Medicine, Louisiana State University, Baton Rouge, Louisiana 70803, USA.
Prostate. 2009 Oct 1;69(14):1586-97. doi: 10.1002/pros.21007.
We evaluated the effect of expressing the cell cycle regulator cdk2ap1, downregulated in prostate cancer cell lines, in inhibiting prostate cancer cell growth.
Expression of cdk2ap1 using a tet-inducible lentiviral system modified growth rate, induced cell cycle arrest and apoptosis and reduced the invasive ability of prostate cancer cell lines, as assayed by cell viability, cell cycle profiling, Caspase 3/7 detection, and matrigel invasion assays. We examined the effect of expressing cdk2ap1 on gene expression profiles of cytokine, invasion, apoptotic, and androgen response pathways using quantitative real-time PCR, and used androgen-responsive reporter gene assays, and methylation-sensitive PCR to examine the mechanism of cdk2ap1 interaction with androgen-responsive pathways.
The expression of cdk2ap1 correlated with a reduction in cellular growth, irrespective of inhibition or stimulation of androgen receptor (AR) signaling pathways. Cell cycle arrest, increased apoptosis, and a reduction in invasiveness phenotypes were observed upon cdk2ap1 expression. Enhanced demethylation at the AR promoter, AR expression increases, and enhanced AR transcriptional activity correlated with cdk2ap1 expression.
Our findings support a novel concept by which cell cycle inhibitor genes can impact prostate cancer phenotypes by restoring a tumor suppressive function to androgen-responsive pathways and this function may involve modulation of a subset of functions of the AR.
我们评估了在前列腺癌细胞系中表达下调的细胞周期调节因子cdk2ap1对抑制前列腺癌细胞生长的作用。
使用四环素诱导的慢病毒系统表达cdk2ap1，通过细胞活力、细胞周期分析、半胱天冬酶3/7检测和基质胶侵袭试验检测其对前列腺癌细胞系生长速率、诱导细胞周期停滞和凋亡以及降低侵袭能力的影响。我们使用定量实时PCR检测表达cdk2ap1对细胞因子、侵袭、凋亡和雄激素反应途径基因表达谱的影响，并使用雄激素反应性报告基因试验和甲基化敏感性PCR检测cdk2ap1与雄激素反应途径相互作用的机制。
无论雄激素受体（AR）信号通路受到抑制还是刺激，cdk2ap1的表达都与细胞生长的减少相关。cdk2ap1表达后观察到细胞周期停滞、凋亡增加和侵袭性表型减少。AR启动子处的去甲基化增强、AR表达增加以及AR转录活性增强与cdk2ap1表达相关。
我们的研究结果支持了一个新的概念，即细胞周期抑制基因可以通过恢复雄激素反应途径的肿瘤抑制功能来影响前列腺癌表型，并且这种功能可能涉及对AR一部分功能的调节。
