Mirzakhani Kimia, Heidari Horestani Mehdi, Kallenbach Julia, Atri Roozbahani Golnaz, Baniahmad Aria
Institute of Human Genetics, Jena University Hospital, Am Klinikum 1, 07740, Jena, Germany.
Biochem Genet. 2024 Nov 19. doi: 10.1007/s10528-024-10953-9.
Clinical trials for prostate cancer (PCa) patients have implemented the bipolar androgen therapy (BAT) that includes the treatment with supraphysiological androgen level (SAL). SAL treatment induces cellular senescence in tumor samples of PCa patients and in various PCa cell lines, including castration-resistant PCa (CRPC), and is associated with enhanced phospho-AKT levels. Using an AKT inhibitor (AKTi), the SAL-mediated cell senescence is inhibited. Here, we show by RNA-seq analyses of two human PCa cell lines, that annexin A2 (ANXA2) expression is induced by SAL and repressed by co-treatment with AKTi. Higher ANXA2 expression is associated with better survival of PCa patients and suggests that ANXA2 is part of SAL-mediated tumor suppressive activity. ChIP-seq revealed that AR is recruited to the intronic regions of ANXA2 gene suggesting that ANXA2 is a novel direct AR target gene. Knockdown of ANXA2 shows that SAL-induced cellular senescence is mediated by ANXA2 and enhances the levels of phospho-AKT indicating an interaction between the AR, ANXA2 and AKT. Notably, we found that the level of heat shock protein HSP27, known to interact with ANXA2, is associated with cellular senescence. HSP27 level is induced by SAL but the induction is blunted by knockdown of ANXA2 suggesting a novel ANXA2-HSP27 pathway in PCa. This was confirmed using an HSP27 inhibitor that reduced the SAL-induced cellular senescence levels suggesting that ANXA2 upregulates HSP27 to mediate AR-signaling in SAL-induced cellular senescence. Thus, the data indicate ANXA2-HSP27 cross-talk as novel factors in the signaling by the AR-AKT pathway to mediate cellular senescence.
前列腺癌（PCa）患者的临床试验已采用双极雄激素疗法（BAT），其中包括超生理雄激素水平（SAL）治疗。SAL治疗可诱导PCa患者肿瘤样本以及包括去势抵抗性PCa（CRPC）在内的各种PCa细胞系发生细胞衰老，且与磷酸化AKT水平升高有关。使用AKT抑制剂（AKTi）可抑制SAL介导的细胞衰老。在此，我们通过对两个人类PCa细胞系进行RNA测序分析表明，膜联蛋白A2（ANXA2）的表达由SAL诱导，并在与AKTi联合处理时受到抑制。较高的ANXA2表达与PCa患者更好的生存率相关，这表明ANXA2是SAL介导的肿瘤抑制活性的一部分。染色质免疫沉淀测序（ChIP-seq）显示雄激素受体（AR）被招募到ANXA2基因的内含子区域，这表明ANXA2是一个新的直接AR靶基因。敲低ANXA2表明SAL诱导的细胞衰老由ANXA2介导，并提高了磷酸化AKT的水平，这表明AR、ANXA2和AKT之间存在相互作用。值得注意的是，我们发现已知与ANXA2相互作用的热休克蛋白HSP27的水平与细胞衰老有关。HSP27水平由SAL诱导，但在敲低ANXA2后诱导作用减弱，这表明在PCa中存在一条新的ANXA2-HSP27途径。使用HSP27抑制剂可降低SAL诱导的细胞衰老水平，从而证实了这一点，这表明ANXA2上调HSP27以介导SAL诱导的细胞衰老中的AR信号传导。因此这些数据表明ANXA2-HSP信号串扰是AR-AKT途径信号传导中介导细胞衰老的新因素。
