Tang Hailong, Shu Mimi, Dai Bo, Xu Li, Dong Baoxia, Gao Guangxun, Chen Xiequn
a Department of Hematology , Xijing Hospital, Fourth Military Medical University , Xi'an , Shaanxi , China.
b Shaanxi Center for Stem Cell Application Engineering Research , Xi'an , Shaanxi , China.
Leuk Lymphoma. 2018 Sep;59(9):2220-2226. doi: 10.1080/10428194.2017.1413188. Epub 2017 Dec 18.
Acquisition of chemoresistance accounts for a major cause of chemotherapy failure for multiple myeloma (MM). Bone marrow stromal cells (BMSCs) are considered to play a pivotal role in modulating drug resistance of MM cells. However, the underlying mechanism whereby BMSCs, particularly damaged stromal cells, affects chemoresistance has not been identified yet. Here, we show exposure to doxorubicin doxorubicin (Dox) induced dramatic ATM (ataxia-telangiectasia-mutated)-dependent DNA damage response (DDR) and increased secretion of interleukin (IL)-6 in HS-5 cell line and primary BMSCs derived from healthy donors. Specifically, IL-6-containing conditioned media (CM) derived from Dox-pretreated stromal cells displayed significant protective effect on Dox-induced apoptosis of MM cells. Also, treatment of BMSCs with ATM kinase inhibitor markedly reduced IL-6 secretion and concurrently, partially reversed CM-mediated chemoresistance in myeloma cells. These data indicate that DNA-damaging drug triggers an ATM-dependent DDR in BMSCs, leading to increased cytokine secretion and resistance of myeloma cells to chemotherapy-induced apoptosis.
获得化学抗性是多发性骨髓瘤（MM）化疗失败的主要原因。骨髓基质细胞（BMSC）被认为在调节MM细胞的耐药性中起关键作用。然而，BMSC，特别是受损的基质细胞影响化学抗性的潜在机制尚未明确。在此，我们发现，阿霉素（Dox）处理可诱导HS-5细胞系和来自健康供体的原代BMSC中发生显著的依赖于共济失调毛细血管扩张突变（ATM）的DNA损伤反应（DDR），并增加白细胞介素（IL）-6的分泌。具体而言，来自经Dox预处理的基质细胞的含IL-6的条件培养基（CM）对Dox诱导的MM细胞凋亡具有显著的保护作用。此外，用ATM激酶抑制剂处理BMSC可显著降低IL-6的分泌，同时部分逆转CM介导的骨髓瘤细胞化学抗性。这些数据表明，DNA损伤药物在BMSC中触发了依赖于ATM的DDR，导致细胞因子分泌增加以及骨髓瘤细胞对化疗诱导的凋亡产生抗性。
