真核起始因子4F(eIF4F)复合物在蛋白质翻译起始中起着关键作用;然而,它在恶性和良性雪旺细胞肿瘤中的重要性尚未被探索,阻断eIF4F功能是否有效治疗这些肿瘤尚不清楚。
对人类恶性外周神经鞘瘤(MPNST)和前庭神经鞘瘤(VS)进行eIF4F成分的免疫染色。通过RNA干扰评估eIF4A和eIF4E在细胞生长中的作用。筛选各种天然化合物的生长抑制活性。进行流式细胞术和Western印迹以表征西维雌酚的作用,并在原位小鼠模型中验证了其抗肿瘤活性。
MPNST和VS经常过表达eIF4A,eIF4E,和/或eIF4G。eIF4A1、eIF4A2和eIF4E的耗尽显著降低了MPNST细胞生长。通过筛选一组植物衍生化合物,在MPNST和VS细胞中,eIF4A抑制剂silvestrol被鉴定为具有纳摩尔IC50值的先导药物.Silvestrol在NF1缺陷型和NF1表达型MPNST细胞和原代VS细胞中诱导G2/M阻滞。Silvestrol持续降低多种细胞周期蛋白的水平,奥罗拉A,和有丝分裂激酶AKT和ERK。在NF1(-/-)MPNST和Nf2(-/-)神经鞘瘤的小鼠模型中,西维雌酚治疗显著抑制肿瘤生长。这种减少的肿瘤生长伴随着磷酸化组蛋白H3和TUNEL标记的升高,与silvestrol处理的肿瘤细胞的G2/M阻滞和凋亡一致。
eIF4F复合物是MPNST和VS的潜在治疗靶点,和silvestrol可能是治疗这些肿瘤的有前途的药物。
The eukaryotic initiation factor 4F (eIF4F) complex plays a pivotal role in protein translation initiation; however, its importance in malignant and benign Schwann cell tumors has not been explored, and whether blocking eIF4F function is effective for treating these tumors is not known.
Immunostaining was performed on human malignant peripheral nerve sheath tumors (MPNSTs) and vestibular schwannomas (VSs) for eIF4F components. The role of eIF4A and eIF4E in cell growth was assessed by RNA interference. Various natural compounds were screened for their growth-inhibitory activity. Flow cytometry and Western blotting were performed to characterize the action of silvestrol, and its antitumor activity was verified in orthotopic mouse models.
MPNSTs and VSs frequently overexpressed eIF4A, eIF4E, and/or eIF4G. Depletion of eIF4A1, eIF4A2, and eIF4E substantially reduced MPNST cell growth. From screening a panel of plant-derived compounds, the eIF4A inhibitor silvestrol was identified as a leading agent with nanomolar IC50 values in MPNST and VS cells. Silvestrol induced G2/M arrest in both NF1-deficient and NF1-expressing MPNST cells and primary VS cells. Silvestrol consistently decreased the levels of multiple cyclins, Aurora A, and mitogenic kinases AKT and ERKs. Silvestrol treatment dramatically suppressed tumor growth in mouse models for NF1(-/-) MPNST and Nf2(-/-) schwannoma. This decreased tumor growth was accompanied by elevated phospho-histone H3 and TUNEL labeling, consistent with G2/M arrest and apoptosis in silvestrol-treated tumor cells.
The eIF4F complex is a potential therapeutic target in MPNSTs and VS, and silvestrol may be a promising agent for treating these tumors.