Jang Samuel, Janssen Andrew, Aburjania Zviadi, Robers Matthew B, Harrison April, Dammalapati Ajitha, Cheng Yi-Qiang, Chen Herbert, Jaskula-Sztul Renata
Howard Hughes Medical Institute, Birmingham, AL, USA.
Department of Surgery, School of Medicine, University of Alabama, Birmingham, AL, USA.
Oncotarget. 2017 Aug 7;8(41):70828-70840. doi: 10.18632/oncotarget.19993. eCollection 2017 Sep 19.
Novel therapies for neuroendocrine (NE) cancers are desperately needed as they frequently present as metastatic disease and cause debilitating symptoms by secreting excessive hormones. Induction of Notch isoforms has a tumor suppressive effect in NE cancer cell lines, and we have observed that histone deacetylase inhibitors (HDACi) potently activate Notch. In this study, we describe the potential for -derived class I HDACi thailandepsin A (TDP-A) as a Notch activator and therapeutic agent against NE cancer. IC for TDP-A was determined to be 4-6 nM in NE cancer cell lines (BON, MZ-CRC-1, and TT) without cytotoxicity to lung fibroblasts. The binding characteristics of TDP-A to its target HDAC1 was examined using bioluminescence resonance energy transfer (BRET). Western blot and flow cytometry analysis showed that TDP-A induces cell cycle arrest and apoptosis in a dose-dependent manner. TDP-A dose-dependently activated the Notch pathway as measured by increasing functional CBF1-luciferase reporter signal and mRNA and protein expressions of Notch isoforms, which were attenuated by pretreatment with γ-secretase inhibitor DAPT. Furthermore, TDP-A lead to changes in expression level of downstream targets of Notch pathway and reduced expression of NE cancer markers. An study demonstrated that TDP-A suppressed NE cancer progression. These results show that TDP-A, as a Notch activator, is a promising agent against NE cancers.
由于神经内分泌（NE）癌常常以转移性疾病的形式出现，并通过分泌过多激素导致使人衰弱的症状，因此迫切需要新型治疗方法。Notch亚型的诱导在NE癌细胞系中具有肿瘤抑制作用，并且我们已经观察到组蛋白去乙酰化酶抑制剂（HDACi）能有效激活Notch。在本研究中，我们描述了源自泰国的I类HDACi泰国菌素A（TDP-A）作为Notch激活剂和抗NE癌治疗药物的潜力。在NE癌细胞系（BON、MZ-CRC-1和TT）中确定TDP-A的IC为4-6 nM，且对肺成纤维细胞无细胞毒性。使用生物发光共振能量转移（BRET）检测TDP-A与其靶标HDAC1的结合特性。蛋白质印迹和流式细胞术分析表明，TDP-A以剂量依赖的方式诱导细胞周期停滞和凋亡。通过增加功能性CBF1-荧光素酶报告信号以及Notch亚型的mRNA和蛋白质表达来衡量，TDP-A以剂量依赖的方式激活Notch通路，而用γ-分泌酶抑制剂DAPT预处理可减弱这种激活作用。此外，TDP-A导致Notch通路下游靶标的表达水平发生变化，并降低NE癌标志物的表达。一项体内研究表明，TDP-A可抑制NE癌的进展。这些结果表明，TDP-A作为一种Notch激活剂，是一种有前景的抗NE癌药物。
