Institute of Human Genetics, Jena University Hospital, Am Klinikum 1, 07740 Jena, Germany.
Leibniz Institute on Aging, Beutenbergstraße 11, 07745 Jena, Germany.
Biomolecules. 2022 Jul 29;12(8):1048. doi: 10.3390/biom12081048.
The bipolar androgen therapy (BAT) includes the treatment of prostate cancer (PCa) patients with supraphysiological androgen level (SAL). Interestingly, SAL induces cell senescence in PCa cell lines as well as ex vivo in tumor samples of patients. The SAL-mediated cell senescence was shown to be androgen receptor (AR)-dependent and mediated in part by non-genomic AKT signaling. RNA-seq analyses compared with and without SAL treatment as well as by AKT inhibition (AKTi) revealed a specific transcriptome landscape. Comparing the top 100 genes similarly regulated by SAL in two human PCa cell lines that undergo cell senescence and being counteracted by AKTi revealed 33 commonly regulated genes. One gene, ERBB receptor feedback inhibitor 1 (), encodes the mitogen-inducible gene 6 (MIG6) that is potently upregulated by SAL, whereas the combinatory treatment of SAL with AKTi reverses the SAL-mediated upregulation. Functionally, knockdown of enhances the pro-survival AKT pathway by enhancing phosphorylation of AKT and the downstream AKT target S6, whereas the phospho-retinoblastoma (pRb) protein levels were decreased. Further, the expression of the cell cycle inhibitor p15 is enhanced by SAL and knockdown. In line with this, cell senescence is induced by knockdown and is enhanced slightly further by SAL. Treatment of SAL in the knockdown background enhances phosphorylation of both AKT and S6 whereas pRb becomes hypophosphorylated. Interestingly, the knockdown does not reduce AR protein levels or AR target gene expression, suggesting that MIG6 does not interfere with genomic signaling of AR but represses androgen-induced cell senescence and might therefore counteract SAL-induced signaling. The findings indicate that SAL treatment, used in BAT, upregulates MIG6, which inactivates both pRb and the pro-survival AKT signaling. This indicates a novel negative feedback loop integrating genomic and non-genomic AR signaling.
双相雄激素治疗（BAT）包括用超生理雄激素水平（SAL）治疗前列腺癌（PCa）患者。有趣的是，SAL 诱导 PCa 细胞系以及患者肿瘤样本中的细胞衰老。SAL 介导的细胞衰老被证明是雄激素受体（AR）依赖性的，部分是通过非基因组 AKT 信号介导的。与 SAL 处理、AKT 抑制（AKTi）比较的 RNA-seq 分析揭示了特定的转录组图谱。比较两个经历细胞衰老并被 AKTi 拮抗的人前列腺癌细胞系中同样受 SAL 调节的前 100 个基因，发现了 33 个共同调节的基因。一个基因，表皮生长因子受体反馈抑制剂 1（），编码有丝分裂原诱导基因 6（MIG6），SAL 强烈上调该基因，而 SAL 与 AKTi 的联合治疗逆转了 SAL 介导的上调。功能上，下调 增强了 AKT 途径的促生存作用，增强了 AKT 的磷酸化和下游 AKT 靶标 S6，而磷酸化视网膜母细胞瘤（pRb）蛋白水平降低。此外，SAL 和 下调增强了细胞周期抑制剂 p15 的表达。与此一致，下调 诱导细胞衰老，并被 SAL 略微增强。在 下调背景下用 SAL 处理增强了 AKT 和 S6 的磷酸化，而 pRb 变得低磷酸化。有趣的是，下调不会降低 AR 蛋白水平或 AR 靶基因表达，表明 MIG6 不干扰 AR 的基因组信号，而是抑制雄激素诱导的细胞衰老，因此可能拮抗 SAL 诱导的信号。这些发现表明，BAT 中使用的 SAL 治疗上调了 MIG6，它使 pRb 和促生存 AKT 信号失活。这表明了一种新的负反馈环，整合了基因组和非基因组 AR 信号。
