Werner helicase is required for proliferation and DNA damage repair in multiple myeloma
Werner helicase is required for proliferation and DNA damage repair in multiple myeloma
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DOI：
10.1007/s11033-022-08178-3
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发表时间：
2022-12-14
影响因子：
2.8
通讯作者：
Beksac, Meral
中科院分区：
文献类型：
--
作者：
Akcora-Yildiz, Dilara;Ozkan, Tulin;Beksac, Meral
背景 多发性骨髓瘤 (MM) 是一种浆细胞恶性肿瘤，其特征是广泛的基因组不稳定性和异常的 DNA 损伤修复，这是由于骨髓中产生单克隆抗体的浆细胞过度增殖所致。尽管随着新型治疗药物的开发，患者的生存率得到了显着改善，但多发性骨髓瘤仍然是一种无法治愈的疾病。 Werner (WRN) 解旋酶是 RecQ 解旋酶家族的成员，有助于 DNA 复制、重组和修复，在癌细胞存活中已得到重视，但 WRN 在 MM 中的作用和机制仍不清楚。方法和结果 qPCR 检测新诊断和复发 CD138+ 骨髓瘤浆细胞中 WRN mRNA 表达高于正常 CD138+ 浆细胞及其匹配的 CD138- 非致瘤细胞。使用 NSC19630（一种特定的 WRN 解旋酶抑制剂），我们通过 MTT 测定、细胞周期测定、细胞凋亡测定和蛋白质印迹进一步显示 MM 细胞的细胞活力、增殖和 DNA 修复降低，DNA 损伤和细胞凋亡增加。结论 本研究结果表明，WRN 对于 MM 细胞活力、增殖和基因组稳定性至关重要，表明其抑制可能会增强 MM 化疗的疗效。
Background Multiple myeloma (MM), characterized by extensive genomic instability and aberrant DNA damage repair, is a plasma cell malignancy due to the excessive proliferation of monoclonal antibody-producing plasma cells in the bone marrow. Despite the significant improvement in the survival of patients with the development of novel therapeutic agents, MM remains an incurable disease. Werner (WRN) helicase, a member of the RecQ helicase family that contributes to DNA replication, recombination, and repair, has been highlighted in cancer cell survival, yet the role and mechanism of WRN in MM remain unclear. Methods and results Increased mRNA expression of WRN in newly diagnosed and relapsed CD138+ myeloma plasma cells than normal CD138+ plasma cells and their matched CD138- non-tumorigenic cells were detected by qPCR. Using NSC19630, a specific WRN helicase inhibitor, we further showed decreased cell viability, proliferation, and DNA repair and increased DNA damage and apoptosis in MM cells by MTT assay, cell cycle assay, apoptosis assay, and Western blotting. Conclusions The results of the present study demonstrate that WRN is essential in MM cell viability, proliferation, and genomic stability, indicating its inhibition may enhance the efficacy of chemotherapy in MM.