Histone deacetylase inhibitor AR-42 differentially affects cell-cycle transit in meningeal and meningioma cells, potently inhibiting NF2-deficient meningioma growth.
Histone deacetylase inhibitor AR-42 differentially affects cell-cycle transit in meningeal and meningioma cells, potently inhibiting NF2-deficient meningioma growth.
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DOI：
10.1158/0008-5472.can-12-1888
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发表时间：
2013-01-15
期刊：
影响因子：
11.2
通讯作者：
Chang LS
中科院分区：
文献类型：
--
作者：
Burns SS;Akhmametyeva EM;Oblinger JL;Bush ML;Huang J;Senner V;Chen CS;Jacob A;Welling DB;Chang LS
脑膜瘤占原发性颅内肿瘤的约34%，与NF 2患者的死亡率增加相关。为了评估这些肿瘤的潜在药物治疗，我们建立了一个可量化的NF 2缺陷型脑膜瘤原位模型。我们发现，端粒酶永生化的Ben-Men-1良性脑膜瘤细胞在NF 2外显子7处有一个单核苷酸缺失，并且不表达NF 2蛋白，merlin。我们还证明，泛组蛋白脱乙酰酶抑制剂AR-42通过增加p16 INK 4A、p21 CIP 1/WAF 1和p27 KIP 1的表达来抑制Ben-Men-1和正常脑膜细胞的增殖。此外，AR-42增加促凋亡Bim表达并降低抗凋亡BclXL水平。然而，AR-42主要将Ben-Men-1细胞阻滞在G2/M，而在脑膜细胞中诱导细胞周期阻滞在G1。一致地，AR-42显著降低脑膜细胞中的细胞周期蛋白D1、E和A以及PCNA的水平，同时显著降低Ben-Men-1细胞中的细胞周期蛋白B的表达，这对于通过G2的进展是重要的。此外，AR-42降低Aurora A和B表达。为了比较AR-42和AR-12（一种PDK 1抑制剂）的体内功效，我们生成并使用表达胰蛋白酶的Ben-Men-1-LucB细胞来建立随时间生长的颅内异种移植物。虽然AR-12治疗适度减缓了肿瘤生长，但AR-42导致Ben-Men-1-LucB肿瘤消退。重要的是，AR-42治疗的肿瘤在异种移植小鼠转为正常饮食时显示出最小的再生长。总之，这些结果表明AR-42是脑膜瘤的潜在治疗方法。AR-42对正常脑膜和脑膜瘤细胞的细胞周期进展的差异效应可能暗示了为什么AR-42在有效抑制肿瘤生长的同时耐受性良好。
Meningiomas constitute ~34% of primary intracranial tumors and are associated with increased mortality in NF2 patients. To evaluate potential medical therapies for these tumors, we have established a quantifiable orthotopic model for NF2-deficient meningiomas. We showed that telomerase-immortalized Ben-Men-1 benign meningioma cells harbored a single nucleotide deletion in NF2 exon 7 and did not express the NF2 protein, merlin. We also demonstrated that AR-42, a pan-histone deacetylase inhibitor, inhibited proliferation of both Ben-Men-1 and normal meningeal cells by increasing expression of p16INK4A, p21CIP1/WAF1, and p27KIP1. Also, AR-42 increased pro-apoptotic Bim expression and decreased anti-apoptotic BclXL levels. However, AR-42 predominantly arrested Ben-Men-1 cells at G2/M, while inducing cell-cycle arrest at G1 in meningeal cells. Consistently, AR-42 substantially decreased the levels of cyclin D1, E, and A, and PCNA in meningeal cells while significantly reducing the expression of cyclin B, important for progression through G2, in Ben-Men-1 cells. In addition, AR-42 decreased Aurora A and B expression. To compare the in vivo efficacies of AR-42 and AR-12, a PDK1 inhibitor, we generated and used luciferase-expressing Ben-Men-1-LucB cells to establish intracranial xenografts that grew over time. While AR-12 treatment moderately slowed tumor growth, AR-42 caused regression of Ben-Men-1-LucB tumors. Importantly, AR-42-treated tumors showed minimal regrowth when xenograft-bearing mice were switched to normal diet. Together, these results suggest that AR-42 is a potential therapy for meningiomas. The differential effect of AR-42 on cell-cycle progression of normal meningeal and meningioma cells may have implications for why AR-42 is well-tolerated while it potently inhibits tumor growth.