Jendrossek Verena, Henkel Marco, Hennenlotter Jörg, Vogel Ulrich, Ganswindt Ute, Müller Ilka, Handrick Rene, Anastasiadis Aristoteles G, Kuczyk Markus, Stenzl Arnulf, Belka Claus
CCC Tübingen, Center of Urogenital Oncology, Department of Radiation Oncology, Essen, Germany.
BJU Int. 2008 Aug;102(3):371-82. doi: 10.1111/j.1464-410X.2008.07703.x. Epub 2008 May 12.
To provide a rational basis for targeted treatment approaches in prostate cancer deregulation of the phosphatidylinositol-3-kinase (PI3K)/protein kinase B (PKB/Akt) system was analysed.
In all, 45 patients with primary localized prostate cancer that underwent radical prostatectomy were included in the present study. Upon scoring of the pathological grade, expression and phosphorylation levels of PKB/Akt and relevant downstream targets were determined in tissue specimens by immunohistochemistry using specific antibodies against PTEN, PKB/Akt, its downstream targets, and the respective phosphorylated proteins.
Most patients (>90%) had up-regulated expression and/or phosphorylation of PKB/Akt in the malignant tissue compared with the surrounding benign tissue, with a higher prevalence of increased phosphorylated PKB/Akt in patients with Gleason scores of > or =6 (100%) compared with those with Gleason scores of 4-5 (five of 13 patients), and in particular in patients with clinical progression. Up-regulated phosphorylation of PKB/Akt occurred either in association with loss or inactivation of PTEN or in a PTEN-independent manner. Enhanced phosphorylation levels of the PKB/Akt substrates glycogen synthase kinase 3, the mammalian target of rapamycin or the forkhead transcription factor like 1 (FKHRL1) were found in 29%, 42% and 40% of the tumours, respectively. Of these, only increased phosphorylated-FKHRL1 levels correlated with clinical progression. Interestingly, 80% of patients had a notable overexpression but not phosphorylation of the eucaryotic initiation factor 4E binding protein.
Deregulation of p-PKB/Akt is common in localized prostate cancer and has a putative value as predictive marker for disease progression and as therapeutic target. However, as a consequence of the substantial heterogeneity in the expression and phosphorylation levels of relevant PKB/Akt effector pathways, for a rational use of specified inhibitors of the PI3K/PKB system a complex pattern testing of expression and activity of the respective target proteins for prediction of efficacy and prognosis seems mandatory.
通过分析磷脂酰肌醇-3-激酶（PI3K）/蛋白激酶B（PKB/Akt）系统失调情况，为前列腺癌的靶向治疗方法提供合理依据。
本研究共纳入45例接受根治性前列腺切除术的原发性局限性前列腺癌患者。在对病理分级进行评分后，使用针对PTEN、PKB/Akt及其下游靶点以及相应磷酸化蛋白的特异性抗体，通过免疫组织化学法测定组织标本中PKB/Akt及相关下游靶点的表达和磷酸化水平。
与周围良性组织相比，大多数患者（>90%）的恶性组织中PKB/Akt的表达和/或磷酸化上调，Gleason评分≥6分的患者中磷酸化PKB/Akt增加的发生率更高（100%），而Gleason评分为4 - 5分的患者中（13例患者中的5例）则较低，尤其是临床进展患者。PKB/Akt磷酸化上调要么与PTEN缺失或失活相关，要么以不依赖PTEN的方式发生。分别在29%、42%和40%的肿瘤中发现PKB/Akt底物糖原合酶激酶3、雷帕霉素哺乳动物靶点或叉头转录因子样1（FKHRL1）的磷酸化水平增强。其中，只有磷酸化FKHRL1水平升高与临床进展相关。有趣的是，80%的患者真核起始因子4E结合蛋白有显著过表达但无磷酸化。
p-PKB/Akt失调在局限性前列腺癌中很常见，作为疾病进展的预测标志物和治疗靶点具有推定价值。然而，由于相关PKB/Akt效应通路的表达和磷酸化水平存在大量异质性，为合理使用PI3K/PKB系统的特定抑制剂，对各自靶蛋白的表达和活性进行复杂模式检测以预测疗效和预后似乎是必要的。
