β-TrCP Inhibition Reduces Prostate Cancer Cell Growth via Upregulation of the Aryl Hydrocarbon Receptor

BackgroundProstate cancer is a common and heterogeneous disease, where androgen receptor (AR) signaling plays a pivotal role in development and progression. The initial treatment for advanced prostate cancer is suppression of androgen signaling. Later on, essentially all patients develop an androgen independent stage which does not respond to anti hormonal treatment. Thus, alternative strategies targeting novel molecular mechanisms are required. β-TrCP is an E3 ligase that targets various substrates essential for many aspects of tumorigenesis.
Methodology/Principal FindingsHere we show that β-TrCP depletion suppresses prostate cancer and identify a relevant growth control mechanism. shRNA targeted against β-TrCP reduced prostate cancer cell growth and cooperated with androgen ablation in vitro and in vivo. We found that β-TrCP inhibition leads to upregulation of the aryl hydrocarbon receptor (AhR) mediating the therapeutic effect. This phenomenon could be ligand independent, as the AhR ligand 2,3,7,8-Tetrachlorodibenzo-p-Dioxin (TCDD) did not alter prostate cancer cell growth. We detected high AhR expression and activation in basal cells and atrophic epithelial cells of human cancer bearing prostates. AhR expression and activation is also significantly higher in tumor cells compared to benign glandular epithelium.
Conclusions/SignificanceTogether these observations suggest that AhR activation may be a cancer counteracting mechanism in the prostate. We maintain that combining β-TrCP inhibition with androgen ablation could benefit advanced prostate cancer patients.

背景
前列腺癌是一种常见且具有异质性的疾病，雄激素受体（androgen receptor，AR）信号通路在其发生与进展过程中发挥关键作用。晚期前列腺癌的初始治疗方案为抑制雄激素信号通路。此后，几乎所有患者都会进展为雄激素非依赖期，该阶段对抗激素治疗无响应。因此，亟需靶向新型分子机制的替代治疗策略。β-TrCP是一类E3泛素连接酶（E3 ligase），可靶向肿瘤发生多个环节所必需的多种底物蛋白。
方法学/主要研究结果
本研究证实，β-TrCP敲低可抑制前列腺癌增殖，并明确了一条相关的生长调控机制。靶向β-TrCP的短发夹RNA（short hairpin RNA，shRNA）可降低前列腺癌细胞的增殖能力，并在体内外实验中与雄激素剥夺治疗发挥协同作用。研究发现，β-TrCP抑制可导致芳香烃受体（aryl hydrocarbon receptor，AhR）的表达上调，从而介导该治疗效应。该效应不依赖于配体，因为芳香烃受体配体2,3,7,8-四氯二苯并对二噁英（2,3,7,8-Tetrachlorodibenzo-p-Dioxin，TCDD）并未改变前列腺癌细胞的增殖状态。我们在人类前列腺癌组织的基底细胞与萎缩性上皮细胞中检测到高水平的AhR表达与活化。与良性腺上皮相比，肿瘤细胞中的AhR表达与活化水平同样显著升高。
结论与意义
综上，上述研究结果提示，AhR活化可能是前列腺内的一种抗肿瘤防御机制。本研究认为，将β-TrCP抑制与雄激素剥夺治疗联合应用，可使晚期前列腺癌患者获益。