Department of Biochemistry and Molecular Biology, College of Medicine, University of Nebraska Medical Center, Omaha, Nebraska, United States of America.
PLoS One. 2012;7(2):e31919. doi: 10.1371/journal.pone.0031919. Epub 2012 Feb 23.
The progression of prostate cancers (PCs) to locally invasive, androgen-independent and metastatic disease states is generally associated with treatment resistance and disease relapse. The present study was undertaken to establish the possibility of using a combination of specific oncogenic products, including epidermal growth factor receptor (EGFR), pAkt, nuclear factor-kappaB (NF-κB) and macrophage inhibitory cytokine-1 (MIC-1) as biomarkers and therapeutic targets for optimizing the management of patients with localized PC at earlier disease stages. The immunohistochemical and immunofluorescence data have revealed that the expression levels of EGFR, Ser(473)-pAkt, NF-κB p65 and MIC-1 proteins were significantly enhanced in the same subset of 76 cases of prostatic adenocarcinoma specimens during the disease progression and these biomarkers were expressed in a small subpopulation of CD133(+) PC cells and the bulk tumor mass of CD133(-) PC cells. Importantly, all of these biomarkers were also overexpressed in 80-100% of 30 PC metastasis bone tissue specimens. Moreover, the results have indicated that the EGF-EGFR signaling pathway can provide critical functions for the self-renewal of side population (SP) cells endowed with stem cell-like features from highly invasive WPE1-NB26 cells. Of therapeutic interest, the targeting of EGFR, pAkt, NF-κB or MIC-1 was also effective at suppressing the basal and EGF-promoted prostasphere formation by SP WPE1-NB26 cells, inducing disintegration of SP cell-derived prostaspheres and decreasing the viability of SP and non-SP WPE1-NB26 cell fractions. Also, the targeting of these oncogenic products induced the caspase-dependent apoptosis in chemoresistant SP WPE1-NB26 cells and enhanced their sensibility to the cytotoxic effects induced by docetaxel. These findings suggest that the combined use of EGFR, pAkt, NF-κB and/or MIC-1 may represent promising strategies for improving the accuracy of current diagnostic and prognostic methods and efficacy of treatments of PC patients in considering the disease heterogeneity, thereby preventing PC progression to metastatic and lethal disease states.
前列腺癌（PC）向局部侵袭性、雄激素非依赖性和转移性疾病状态的进展通常与治疗抵抗和疾病复发有关。本研究旨在探讨使用特定致癌产物（包括表皮生长因子受体（EGFR）、pAkt、核因子-kappaB（NF-κB）和巨噬细胞抑制细胞因子-1（MIC-1））作为生物标志物和治疗靶点的可能性，以优化局部 PC 患者在早期疾病阶段的管理。免疫组织化学和免疫荧光数据显示，在同一组 76 例前列腺腺癌标本中，EGFR、Ser（473）-pAkt、NF-κB p65 和 MIC-1 蛋白的表达水平在疾病进展过程中显著增强，这些生物标志物在 CD133（+）PC 细胞的一小部分亚群和 CD133（-）PC 细胞的肿瘤块中表达。重要的是，所有这些生物标志物在 30 例 PC 转移骨组织标本的 80-100%中也过表达。此外，研究结果表明，EGF-EGFR 信号通路可为具有干细胞样特征的侧群（SP）细胞的自我更新提供关键功能，这些细胞来自高侵袭性 WPE1-NB26 细胞。有趣的是，靶向 EGFR、pAkt、NF-κB 或 MIC-1 也能有效抑制 SP WPE1-NB26 细胞的基础和 EGF 促进的前列腺球体形成，诱导 SP 细胞衍生的前列腺球体的解体，并降低 SP 和非 SP WPE1-NB26 细胞亚群的活力。此外，这些致癌产物的靶向作用诱导化学抗性 SP WPE1-NB26 细胞中的 caspase 依赖性凋亡，并增强其对多西紫杉醇诱导的细胞毒性作用的敏感性。这些发现表明，联合使用 EGFR、pAkt、NF-κB 和/或 MIC-1 可能代表一种有前途的策略，可以提高当前诊断和预后方法的准确性，并提高 PC 患者治疗的疗效，同时考虑到疾病异质性，从而防止 PC 进展为转移性和致命性疾病状态。
