Background: Neuroblastoma (NB) remains one of the deadliest pediatric solid tumors. Recent advancements aimed at improving outcomes have been insufficient, and patients with high-risk NB continue to have a poor prognosis. Protein phosphatase 2A (PP2A) is a tumor suppressor protein downregulated in many cancers, including NB. PP2A activation has been shown to affect the malignant phenotype in other solid tumors. The present studies aim to investigate the effects of two novel PP2A activators as a NB therapeutic. Methods: Four established NB cell lines and a patient-derived xenoline were utilized to study the effect on cell viability, proliferation, motility, and in vivo tumor growth using two novel tricyclic sulfonamide PP2A activators, ATUX-3364 and ATUX-8385. Results: ATUX-3364 and ATUX-8385 increased PP2A activity. These PP2A activators led to decreased viability, proliferation, and motility of NB cells. Treatment of animals bearing NB tumors with ATUX-3364 or ATUX-8385 resulted in decreased tumor growth inMYCN-amplified SK-N-BE(2) tumors. At the molecular level, PP2A-based reactivation led to dephosphorylation of MYCN-S62 and decreased MYCN protein expression. Conclusions: PP2A activators decreased NB cell viability, proliferation, and motility. In vivo experiments show that PP2A activators have more significant effects on tumorigenesis inMYCN-amplifiedtumors. Finally, phosphorylation of MYCN protein was decreased following treatment with novel sulfonamide PP2A activators. These data and mechanistic insights may be useful for developing new PP2A-based therapies that target MYCN for the treatment of NB.
背景：神经母细胞瘤（NB）仍是致死率最高的儿童实体肿瘤之一。近期旨在改善预后的研究进展仍显不足，高危NB患者的预后依然较差。蛋白磷酸酶2A（PP2A）是一种在包括NB在内的多种癌症中表达下调的肿瘤抑制蛋白。已有研究表明PP2A激活可影响其他实体肿瘤的恶性表型。本研究旨在探讨两种新型PP2A激活剂作为NB治疗药物的效果。方法：采用四种已建立的NB细胞系和患者来源的异种移植细胞系，使用两种新型三环磺酰胺类PP2A激活剂ATUX-3364和ATUX-8385，研究其对细胞活力、增殖、迁移能力及体内肿瘤生长的影响。结果：ATUX-3364和ATUX-8385能增强PP2A活性。这些PP2A激活剂导致NB细胞活力、增殖和迁移能力下降。使用ATUX-3364或ATUX-8385治疗携带NB肿瘤的动物，可抑制MYCN扩增型SK-N-BE(2)肿瘤的生长。在分子水平上，基于PP2A的再激活导致MYCN-S62去磷酸化并降低MYCN蛋白表达。结论：PP2A激活剂能降低NB细胞活力、增殖和迁移能力。体内实验表明PP2A激活剂对MYCN扩增型肿瘤的致癌作用具有更显著影响。最后，新型磺酰胺类PP2A激活剂治疗后MYCN蛋白磷酸化水平降低。这些数据及机制研究可能有助于开发靶向MYCN的新型PP2A疗法用于NB治疗。
肿瘤(癌症)患者之家