Dyberg Cecilia, Andonova Teodora, Olsen Thale Kristin, Brodin Bertha, Kool Marcel, Kogner Per, Johnsen John Inge, Wickström Malin
Childhood Cancer Research Unit, Department of Women's and Children's Health, Karolinska Institutet, 171 77 Stockholm, Sweden.
Department of Microbiology Tumor and Cell Biology (MTC), Karolinska Institutet, 171 77 Stockholm, Sweden.
Cancers (Basel). 2019 Dec 26;12(1):73. doi: 10.3390/cancers12010073.
Medulloblastoma is one of the most common malignant brain tumor types in children, with an overall survival of 70%. Mortality is associated with metastatic relapsed tumors. Rho-associated kinases (ROCKs), important for epithelial-mesenchymal transition (EMT) and proper nervous system development, have previously been identified as a promising drug target to inhibit cancer growth and metastatic spread. Here, we show that ROCKs are expressed in medulloblastoma, with higher ROCK2 mRNA expression in metastatic compared to non-metastatic tumors. By evaluating three ROCK inhibitors in a panel of medulloblastoma cell lines we demonstrated that medulloblastoma cells were sensitive for pharmacological ROCK inhibition. The specific ROCK inhibitor RKI-1447 inhibited the tumorigenicity in medulloblastoma cells as well as impeded cell migration and invasion. Differential gene expression analysis suggested that ROCK inhibition was associated with the downregulation of signaling pathways important in proliferation and metastasis e.g., TNFα via NFκβ, TGFβ, and EMT. Expression of key proteins in these pathways such as RHOA, RHOB, JUN, and vimentin was downregulated in ROCK inhibited cells. Finally, we showed that ROCK inhibition by RKI-1447 suppressed medulloblastoma growth and proliferation in vivo. Collectively, our results suggest that ROCK inhibition presents a potential new therapeutic option in medulloblastoma, especially for children with metastatic disease.
髓母细胞瘤是儿童中最常见的恶性脑肿瘤类型之一,总体生存率为70%。死亡率与转移性复发肿瘤相关。Rho相关激酶(ROCKs)对上皮-间质转化(EMT)和正常神经系统发育很重要,此前已被确定为抑制癌症生长和转移扩散的一个有前景的药物靶点。在这里,我们表明ROCKs在髓母细胞瘤中表达,与非转移性肿瘤相比,转移性肿瘤中ROCK2 mRNA表达更高。通过在一组髓母细胞瘤细胞系中评估三种ROCK抑制剂,我们证明髓母细胞瘤细胞对药理学上的ROCK抑制敏感。特异性ROCK抑制剂RKI-1447抑制髓母细胞瘤细胞的致瘤性,并阻碍细胞迁移和侵袭。差异基因表达分析表明,ROCK抑制与增殖和转移中重要的信号通路下调有关,例如通过NFκβ、TGFβ和EMT的TNFα。在ROCK抑制的细胞中,这些通路中的关键蛋白如RHOA、RHOB、JUN和波形蛋白的表达下调。最后,我们表明RKI-1447对ROCK的抑制在体内抑制了髓母细胞瘤的生长和增殖。总的来说,我们的结果表明,ROCK抑制在髓母细胞瘤中提供了一种潜在的新治疗选择,特别是对于患有转移性疾病的儿童。
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