针对人髓母细胞瘤细胞中 STAT3 的上游激酶。

Targeting Upstream Kinases of STAT3 in Human Medulloblastoma Cells.

机构信息

Department of Hematology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China.

Department of Biochemistry and Molecular Biology, School of Medicine, University of Maryland, Baltimore, MD 21201, United States.

出版信息

Curr Cancer Drug Targets. 2019;19(7):571-582. doi: 10.2174/1568009618666181016165604.

BACKGROUND

Medulloblastoma is the most common malignant brain tumor in children. Despite improvement in overall survival rate, it still lacks an effective targeted treatment strategy. The Janus family of cytoplasmic tyrosine kinases (JAKs) and Src kinases, upstream protein kinases of signal transducer and activator of transcription 3 (STAT3), play important roles in medulloblastoma pathogenesis and therefore represent potential therapeutic targets.

METHODS

In this report, we examined the inhibitory efficacy of the JAK1/2 inhibitor, ruxolitinib, the JAK3 inhibitor, tofacitinib and two Src inhibitors, KX2-391 and dasatinib.

RESULTS

These small molecule drugs significantly reduce cell viability and inhibit cell migration and colony formation in human medulloblastoma cells in vitro. Src inhibitors have more potent efficacy than JAK inhibitors in inhibiting medulloblastoma cell migration ability. The Src inhibitors can inhibit both phosphorylation of STAT3 and Src while JAK inhibitors reduce JAK/STAT3 phosphorylation. We also investigated the combined effect of the Src inhibitor, dasatinib with cisplatin. The results show that dasatinib exerts synergistic effects with cisplatin in human medulloblastoma cells through the inhibition of STAT3 and Src.

CONCLUSION

Our results suggest that the small molecule inhibitors of STAT3 upstream kinases, ruxolitinib, tofacitinib, KX2-391, and dasatinib could be novel and attractive candidate drugs for the treatment of human medulloblastoma.

背景

髓母细胞瘤是儿童中最常见的恶性脑肿瘤。尽管总生存率有所提高，但仍缺乏有效的靶向治疗策略。Janus 家族细胞质酪氨酸激酶（JAKs）和Src 激酶是信号转导和转录激活因子 3（STAT3）的上游蛋白激酶，在髓母细胞瘤发病机制中起重要作用，因此代表潜在的治疗靶点。

方法

在本报告中，我们研究了 JAK1/2 抑制剂芦可替尼、JAK3 抑制剂托法替尼和两种 Src 抑制剂 KX2-391 和达沙替尼对人髓母细胞瘤细胞的抑制作用。

结果

这些小分子药物在体外显著降低人髓母细胞瘤细胞的活力，并抑制细胞迁移和集落形成。Src 抑制剂在抑制髓母细胞瘤细胞迁移能力方面比 JAK 抑制剂更有效。Src 抑制剂可抑制 STAT3 和 Src 的磷酸化，而 JAK 抑制剂可降低 JAK/STAT3 的磷酸化。我们还研究了 Src 抑制剂达沙替尼与顺铂联合的效果。结果表明，达沙替尼通过抑制 STAT3 和 Src 与顺铂在人髓母细胞瘤细胞中发挥协同作用。