Central Laboratory, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, P.R. China.
Eur Rev Med Pharmacol Sci. 2020 Sep;24(17):8918-8930. doi: 10.26355/eurrev_202009_22833.
Given that FK506 binding protein 51 (FKBP51) is upregulated in multiple cancers, we designed the present study to characterize its role as well as underlying regulatory mechanisms in glioma in the presence and absence of the chemotherapeutic carmustine (BCNU).
Through lentiviral overexpression and shRNA knockdown of FKBP51, we examined the effects on BT325 glioma cell proliferation, migration and invasion using quantitative reverse transcription PCR (qRT-PCR), CCK-8 assay, flow cytometry, and transwell assay.
The upregulation of FKBP51 resulted in significantly decreased BT325 cell proliferation and cell viability, cell cycle arrest, reduced BCNU chemosensitivity and AKT pathway inactivation. However, FKBP51-overexpressed BT325 cells showed enhanced migration and invasion, which was supported by corresponding increase in phosphorylated IKKα (p-IKKα), MMP-2, and MMP-9 levels, as well as increased NF-κB p65 nuclear translocation. By contrast, FKBP51-suppressed BT325 cells showed excessive proliferation and BCNU resistance due to increased p-AKT activation and attenuated migration and invasion.
We demonstrated that the effects of FKBP51 on BT325 glioma cell proliferation, migration, invasion and BCNU chemosensitization are modulated via the AKT and NF-κB pathways. Furthermore, our findings suggest the potential of FKBP51 as a prognostic glioma biomarker and an indicator of patient response to chemotherapy.
FK506 结合蛋白 51（FKBP51）在多种癌症中上调，因此本研究旨在研究其在存在和不存在化疗药物卡莫司汀（BCNU）的情况下在神经胶质瘤中的作用及其潜在调节机制。
通过慢病毒过表达和 FKBP51 shRNA 敲低，我们使用定量逆转录 PCR（qRT-PCR）、CCK-8 测定、流式细胞术和 Transwell 测定来检查 FKBP51 对 BT325 神经胶质瘤细胞增殖、迁移和侵袭的影响。
FKBP51 的上调导致 BT325 细胞增殖和细胞活力、细胞周期停滞、BCNU 化疗敏感性降低和 AKT 通路失活显著降低。然而，FKBP51 过表达的 BT325 细胞表现出增强的迁移和侵袭能力，这得到了相应增加的磷酸化 IKKα（p-IKKα）、MMP-2 和 MMP-9 水平以及 NF-κB p65 核易位的支持。相比之下，FKBP51 抑制的 BT325 细胞由于 p-AKT 激活增加和迁移和侵袭减弱而表现出过度增殖和 BCNU 耐药性。
我们证明 FKBP51 对 BT325 神经胶质瘤细胞增殖、迁移、侵袭和 BCNU 化疗增敏的影响是通过 AKT 和 NF-κB 途径调节的。此外，我们的研究结果表明 FKBP51 作为神经胶质瘤预后生物标志物和患者对化疗反应的指标的潜力。
