Targeting Androgen Receptor Leads to Suppression of Prostate Cancer via Induction of Autophagy
Targeting Androgen Receptor Leads to Suppression of Prostate Cancer via Induction of Autophagy
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DOI：
10.1016/j.juro.2012.06.004
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发表时间：
2012-10-01
影响因子：
6.6
通讯作者：
Chang, Chawnshang
中科院分区：
文献类型：
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作者：
Jiang, Qi;Yeh, Shuyuan;Chang, Chawnshang
目的：雄激素受体在前列腺癌的发生、发展中起重要作用.通过自噬的细胞死亡也可能有助于前列腺癌的进展。我们确定了雄激素受体在前列腺癌细胞自噬过程中的作用和调节作用。材料和方法：利用一系列形态学方法，如透射电子显微镜，（Sigma（R））和GFP-LC 3荧光显微镜测定，用免疫印迹法检测3对前列腺癌细胞系的自噬过程，探讨其与雄激素受体的关系结果：雄激素受体阳性细胞，如LNCaP或CWRrv 1人前列腺癌细胞中的雄激素受体敲低导致自噬增加。将功能性雄激素受体添加到雄激素受体阴性细胞，如PC 3人前列腺癌细胞，导致自噬减少。这表明雄激素受体可能在调节自噬中起负性作用。机制探讨表明雄激素受体可能通过调节p62表达而抑制自噬。使用雄激素受体降解增强剂ASC-J 9（R）靶向雄激素受体以增加自噬的治疗方法抑制了前列腺癌的生长。结论：研究结果提供了雄激素受体可能通过自噬下调促进前列腺癌细胞生长的证据。通过ASC-J 9靶向雄激素受体可能通过诱导自噬导致肿瘤抑制。这可能代表了一种新的、潜在的前列腺癌治疗方法和机制。
Purpose: Androgen receptor has a critical role in prostate cancer development and progression. Cell death via autophagy may also contribute to prostate cancer progression. We determined the role and regulatory effects of androgen receptor on the autophagy process of prostate cancer cells.Materials and Methods: Using a series of morphological approaches, such as transmission electron microscopy, monodansylcadaverine (Sigma (R)) and GFP-LC3 fluorescence microscopy assay, and Western blot we monitored the autophagic process in 3 pairs of prostate cancer cell lines to study the relationship to androgen receptor signals.Results: Androgen receptor knockdown in androgen receptor positive cells, such as LNCaP or CWRrv1 human prostate cancer cells, led to increased autophagy. Adding functional androgen receptor to androgen receptor negative cells, such as PC3 human prostate cancer cells, resulted in decreased autophagy. This suggests that androgen receptor could have a negative role in regulating autophagy. Mechanism dissection indicated that androgen receptor might repress autophagy via modulation of p62 expression. A therapeutic approach of targeting androgen receptor to increase autophagy using the androgen receptor degradation enhancer ASC-J9 (R) suppressed prostate cancer growth.Conclusions: Findings provide evidence that the androgen receptor might promote prostate cancer cell growth via autophagy down-regulation. Targeting the androgen receptor via ASC-J9 might lead to tumor suppression via the induction of autophagy. This may represent a new, potential therapeutic approach and mechanism for prostate cancer.