Koschny Ronald, Boehm Christina, Sprick Martin R, Haas Tobias L, Holland Heidrun, Xu Li-Xin, Krupp Wolfgang, Mueller Wolf C, Bauer Manfred, Koschny Thomas, Keller Marius, Sinn Peter, Meixensberger Juergen, Walczak Henning, Ganten Tom M
From the Department of Gastroenterology, Heidelberg University Hospital (RK, TMG); German Cancer Research Center, Division of Signaling and Functional Genomics (CB); Department of Cell and Molecular Biology, Faculty of Medicine Mannheim, Heidelberg University (CB); and HI-STEM gGmbH/German Cancer Research Center Heidelberg (MRS), Heidelberg, Germany; National Cancer Institute Regina Elena (TLH), Rome, Italy; Translational Centre for Regenerative Medicine Leipzig and Faculty of Medicine (HH, L-XX) and Departments of Neurosurgery (L-XX, WK, JM) and Neuropathology (WCM, MB), University of Leipzig, Leipzig, Germany; Ames Laboratory-US DOE, and Department of Physics and Astronomy, Iowa State University, Ames, Iowa (TK); Departments of Cardiology (MK) and Pathology (PS), University Hospital Heidelberg, Heidelberg, Germany; and Centre for Cell Death, Cancer and Inflammation, UCL Cancer Institute, London, United Kingdom (HW).
J Neuropathol Exp Neurol. 2014 Nov;73(11):1034-46. doi: 10.1097/NEN.0000000000000129.
A meningioma is the most common primary intracranial tumor in adults. Here, we investigated the therapeutic potential of the tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) in 37 meningiomas. Freshly isolated primary meningioma cells were treated with TRAIL with or without different sensitizing protocols, and apoptotic cell death was then quantified. Mechanisms of TRAIL sensitization were determined by a combination of Western blotting, flow cytometry, receptor complex immunoprecipitation, and siRNA-mediated knockdown experiments. Tumor necrosis factor-related apoptosis-inducing ligand receptor expression was analyzed using immunohistochemistry and quantified by an automated software-based algorithm. Primary tumor cells from 11 (29.7%) tumor samples were sensitive to TRAIL-induced apoptosis, 12 (32.4%) were intermediate TRAIL resistant, and 14 (37.8%) were completely TRAIL resistant. We tested synergistic apoptosis-inducing cotreatment strategies and determined that only the proteasome inhibitor bortezomib potently enhanced expression of the TRAIL receptors TRAIL-R1 and/or TRAIL-R2, the formation of the TRAIL death-inducing signaling complex, and activation of caspases; this treatment resulted in sensitization of all TRAIL-resistant meningioma samples to TRAIL-induced apoptosis. Bortezomib pretreatment induced NOXA expression and downregulated c-FLIP, neither of which caused the TRAIL-sensitizing effect. Native TRAIL receptor expression could not predict primary TRAIL sensitivity. This first report on TRAIL sensitivity of primary meningioma cells demonstrates that TRAIL/bortezomib cotreatment may represent a novel therapeutic option for meningiomas.
脑膜瘤是成人最常见的原发性颅内肿瘤。在此，我们研究了肿瘤坏死因子相关凋亡诱导配体（TRAIL）对37例脑膜瘤的治疗潜力。对新鲜分离的原发性脑膜瘤细胞采用有或无不同致敏方案的TRAIL进行处理，然后对凋亡细胞死亡进行定量分析。通过蛋白质印迹、流式细胞术、受体复合物免疫沉淀和小干扰RNA介导的敲低实验相结合的方法确定TRAIL致敏机制。使用免疫组织化学分析肿瘤坏死因子相关凋亡诱导配体受体表达，并通过基于软件的自动算法进行定量。11个（29.7%）肿瘤样本的原发性肿瘤细胞对TRAIL诱导的凋亡敏感，12个（32.4%）为中度TRAIL抵抗，14个（37.8%）为完全TRAIL抵抗。我们测试了协同诱导凋亡的联合治疗策略，确定只有蛋白酶体抑制剂硼替佐米能有效增强TRAIL受体TRAIL-R1和/或TRAIL-R2的表达、TRAIL死亡诱导信号复合物的形成以及半胱天冬酶的激活；这种治疗使所有TRAIL抵抗的脑膜瘤样本对TRAIL诱导的凋亡敏感。硼替佐米预处理诱导NOXA表达并下调c-FLIP，但两者均未引起TRAIL致敏作用。天然TRAIL受体表达无法预测原发性TRAIL敏感性。这份关于原发性脑膜瘤细胞TRAIL敏感性的首次报告表明，TRAIL/硼替佐米联合治疗可能是脑膜瘤的一种新的治疗选择。
