Wiesehöfer Marc, Czyrnik Elena Dilara, Spahn Martin, Ting Saskia, Reis Henning, Dankert Jaroslaw Thomas, Wennemuth Gunther
Department of Anatomy, University Duisburg-Essen, D-45147 Essen, Germany.
Department of Urology, Lindenhofspital Bern, CHE-3012 Bern, Switzerland.
Cancers (Basel). 2021 Feb 2;13(3):578. doi: 10.3390/cancers13030578.
Patients with advanced prostate carcinoma are often treated with an androgen deprivation therapy but long-term treatment can result in a metastatic castration-resistant prostate cancer. This is a more aggressive, untreatable tumor recurrence often containing areas of neuroendocrine differentiated prostate cancer cells. Using an in vitro model of NE-like cancer cells, it could previously be shown that neuroendocrine differentiation of LNCaP cells leads to a strong deregulation of mRNA and miRNA expression. We observe elevated RNA and protein levels of AKT Serine/Threonine Kinase 3 (AKT3) in neuroendocrine-like LNCaP cells. We used prostate resections from patients with neuroendocrine prostate cancer to validate these results and detect a co-localization of neuroendocrine marker genes with AKT3. Analysis of downstream target genes FOXO3A and GSK3 strengthens the assumption AKT3 may play a role in neuroendocrine differentiation. Overexpression of AKT3 shows an increased survival rate of LNCaP cells after apoptosis induction, which in turn reflects the significance in vivo or for treatment. Furthermore, miR-17, -20b and -106b, which are decreased in neuroendocrine-like LNCaP cells, negatively regulate AKT3 biosynthesis. Our findings demonstrate AKT3 as a potential therapeutic target and diagnostic tool in advanced neuroendocrine prostate cancer and a new mRNA-miRNA interaction with a potential role in neuroendocrine differentiation of prostate cancer.
晚期前列腺癌患者通常接受雄激素剥夺治疗，但长期治疗可能导致转移性去势抵抗性前列腺癌。这是一种更具侵袭性、无法治疗的肿瘤复发，通常包含神经内分泌分化的前列腺癌细胞区域。使用神经内分泌样癌细胞的体外模型，此前已表明LNCaP细胞的神经内分泌分化会导致mRNA和miRNA表达的强烈失调。我们观察到神经内分泌样LNCaP细胞中AKT丝氨酸/苏氨酸激酶3（AKT3）的RNA和蛋白质水平升高。我们使用神经内分泌前列腺癌患者的前列腺切除术来验证这些结果，并检测神经内分泌标记基因与AKT3的共定位。对下游靶基因FOXO3A和GSK3的分析强化了AKT3可能在神经内分泌分化中起作用的假设。AKT3的过表达显示LNCaP细胞在诱导凋亡后的存活率增加，这反过来反映了其在体内或治疗中的重要性。此外，在神经内分泌样LNCaP细胞中减少的miR-17、-20b和-106b对AKT3生物合成具有负调控作用。我们的研究结果表明AKT3是晚期神经内分泌前列腺癌的潜在治疗靶点和诊断工具，以及一种在前列腺癌神经内分泌分化中可能起作用的新的mRNA-miRNA相互作用。
