Targeting MK2 Is a Novel Approach to Interfere in Multiple Myeloma
Targeting MK2 Is a Novel Approach to Interfere in Multiple Myeloma
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靶向 MK2 是一种干扰多发性骨髓瘤的新方法
DOI：
10.3389/fonc.2019.00722
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发表时间：
2019-08-08
影响因子：
4.7
通讯作者：
Gu, Chunyan
中科院分区：
文献类型：
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作者：
Guo, Mengjie;Sun, Dongdong;Gu, Chunyan
MAPKAPK2（MK2）是p38 MAPK的直接底物，是肿瘤治疗的一个重要靶点。然而，很少有研究评估它在多发性骨髓瘤（MM）中的功能。在本研究中，MK2表达的MM患者进行了分析基因表达谱（GEP）和基于阵列的比较基因组杂交（aCGH）。通过MTT法、Western blot法和流式细胞术等体外实验来验证MK2在MM中的作用，并通过小鼠生存实验来解释MK2在体内对MM的影响。MM细胞中MK2基因mRNA水平和MK2基因座的染色体获得量较正常组显著增加。此外，MK2高表达的MM患者与不良结局相关。后续研究显示MK2对MM细胞增殖和耐药性有明显的促进作用。对MK2抑制剂IV的进一步探索揭示了其对MM生长和耐药性的抑制作用，以及改善小鼠模型的存活率。此外，MK2抑制剂IV和关键MM治疗药物（包括硼替佐米、多柔比星或地塞米松）的组合促进了抑制MM细胞增殖的疗效。总之，我们的研究揭示了MK2抑制在MM中的临床相关性，并证明靶向MK2可能为MM提供新的治疗方法。
MAPKAPK2 (MK2), the direct substrate of p38 MAPK, has been well-acknowledged as an attractive drug target for cancer therapy. However, few studies have assessed the functions of it in multiple myeloma (MM). In the present study, MK2 expression of MM patients was analyzed by gene expression profiling (GEP) and array-based comparative genomic hybridization (aCGH). Several experiments in vitro including MTT assay, Western blot and flow cytometry analysis were performed to identify the function of MK2 in MM. In addition, we conducted mouse survival experiments to explain the effects of MK2 on MM in vivo. mRNA level of MK2 and chromosomal gain of MK2 locus in MM cells significantly increased compared to normal samples. Furthermore, MM patients with high expression of MK2 were associated with a poor outcome. Follow-up studies showed that MK2 exerted a remarkably positive effect on MM cell proliferation and drug-resistance. Further exploration focusing on MK2 inhibitor IV revealed its inhibitory action on MM growth and drug-resistance, as well as improving survival in mouse models. In addition, a combination of MK2 inhibitor IV and the key MM therapeutic agents including bortezomib, doxorubicin, or dexamethasone facilitated curative effects on inhibiting MM cell proliferation. Taken together, our study reveals the clinical relevance of MK2 inhibition in MM and demonstrates that targeting MK2 may afford a new therapeutic approach to MM.