Kendall Jed J, Chaney Katherine E, Patel Ami V, Rizvi Tilat A, Largaespada David A, Ratner Nancy
Division of Experimental Hematology and Cancer Biology, Cincinnati Children's Hospital, Department of Pediatrics, University of Cincinnati, Cincinnati, OH 45229, USA.
Department of Pediatrics, Masonic Cancer Center, University of Minnesota, Minneapolis, MN 55455, USA.
Oncotarget. 2016 Aug 16;7(33):53191-53203. doi: 10.18632/oncotarget.10668.
Malignant peripheral nerve sheath tumors (MPNSTs) are soft tissue sarcomas that are a major cause of mortality of Neurofibromatosis type 1 (NF1) patients. MPNST patients have few therapeutic options available and only complete surgical resection can be curative. MPNST formation and survival are dependent on activated β-catenin signaling. The goal of this study was to determine if inhibition of the CK2 enzyme can be therapeutically exploited in MPNSTs, given CK2's role in mainta ining oncogenic phenotypes including stabilization of β-catenin. We found that CK2α is over-expressed in MPNSTs and is critical for maintaining cell survival, as the CK2 inhibitor, CX-4945 (Silmitasertib), and shRNA targeting CK2α each significantly reduce MPNST cell viability. These effects were preceded by loss of critical signaling pathways in MPNSTs, including destabilization of β-catenin and TCF8. CX-4945 administration in vivo slowed tumor growth and extends survival time. We conclude that CK2 inhibition is a promising approach to blocking β-catenin in MPNST cells, although combinatorial therapies may be required for maximal efficacy.
恶性外周神经鞘瘤（MPNSTs）是一种软组织肉瘤，是1型神经纤维瘤病（NF1）患者死亡的主要原因。MPNST患者的治疗选择有限，只有完整的手术切除才能治愈。MPNST的形成和存活依赖于激活的β-连环蛋白信号传导。鉴于CK2在维持包括β-连环蛋白稳定在内的致癌表型中的作用，本研究的目的是确定抑制CK2酶是否可用于MPNST的治疗。我们发现CK2α在MPNST中过度表达，并且对于维持细胞存活至关重要，因为CK2抑制剂CX-4945（Silmitasertib）和靶向CK2α的shRNA均能显著降低MPNST细胞活力。这些作用之前是MPNST中关键信号通路的丧失，包括β-连环蛋白和TCF8的不稳定。体内给予CX-4945可减缓肿瘤生长并延长存活时间。我们得出结论，抑制CK2是阻断MPNST细胞中β-连环蛋白的一种有前景的方法，尽管可能需要联合疗法以达到最大疗效。
