Upregulated expression of BCL-2 in multiple myeloma cells induced by exposure to doxorubicin, etoposide, and hydrogen peroxide
Upregulated expression of BCL-2 in multiple myeloma cells induced by exposure to doxorubicin, etoposide, and hydrogen peroxide
复制标题
DOI：
10.1182/blood.v88.5.1805.bloodjournal8851805
复制
发表时间：
1996-09-01
期刊：
影响因子：
20.3
通讯作者：
Lichtenstein, A
中科院分区：
文献类型：
--
作者：
Tu, YP;Xu, FH;Lichtenstein, A
抗凋亡基因BCL-2的表达增强可能参与了化疗耐药。为了确定暴露于化疗中的多发性骨髓瘤细胞是否会改变其BCL-2的表达，我们对骨髓瘤细胞系8226、IM-9和U266以及原发骨髓瘤细胞培养物进行了不同的损伤剂处理。流式细胞术和Western blot分析显示，阿霉素、依托泊苷和过氧化氢在所有骨瘤靶细胞类型中均可诱导浓度依赖性和时间依赖性的BCL-2表达上调。相比之下，血清饥饿、地塞米松和抗fas抗体对表达没有影响。BCL-2的表达增强是相对选择性的，因为处理对ig轻链、BCL-X或肌动蛋白的表达没有影响。逆转录聚合酶链反应试验显示，早在阿霉素治疗4小时后，8226细胞中BCL-2 RNA水平就增加了，而细胞恢复率并未降低。因此，阿霉素刺激单个8226细胞中BCL-2的表达，而不是简单地让高表达BCL-2的细胞在培养中存活。阿霉素处理的BCL-2表达上调的8226细胞对阿霉素第二次暴露相对耐药。此外，转染BCL-2的IM-9细胞对阿霉素和依托泊苷的细胞毒性具有抗性，BCL-2的表达增强，与初始暴露于阿霉素时的表达增强相当。这些数据表明，暴露于化疗药物可能会增强存活的骨髓瘤细胞中BCL-2的表达，并有助于获得性化疗耐药。(C) 1996年由美国血液病学会出版。
Enhanced expression of the antiapoptotic gene BCL-2 may participate in chemoresistance. To ascertain if multiple myeloma cells surviving exposure to chemotherapy alter their BCL-2 expression, we treated the myeloma cell lines 8226, IM-9, and U266 as well as a primary myeloma cell culture with various injurious agents. Doxorubicin, etoposide, and hydrogen peroxide consistently induced a concentration- and time-dependent upregulation of BCL-2 expression in all myeloma target cell types assayed by flow cytometry and Western blot analysis. In contrast, serum starvation, dexamethasone, and anti-fas antibodies had no effect on expression. Enhanced expression of BCL-2 was relatively selective as treatments had no effect on expression of ig light chains, BCL-X, or actin. An reverse transcriptase-polymerase chain reaction assay showed increased levels of BCL-2 RNA in 8226 cells as early as 4 hours after treatment with doxorubicin at a time when cell recoveries were not decreased, Thus, doxorubicin stimulates BCL-2 expression in individual 8226 cells rather than simply allowing a selected survival of high BCL-2-expressing cells in culture, Doxorubicin-treated 8226 cells with upregulated BCL-2 expression were relatively resistant to a second exposure of doxorubicin. In addition, BCL-2-transfected IM-9 cells, with enhanced expression of BCL-2 which was comparable to that achieved by initial exposure to doxorubicin, were resistant to doxorubicin and etoposide cytotoxicity. These data suggest that exposure to chemotherapeutic agents may enhance BCL-2 expression in surviving myeloma cells and contribute to acquired chemoresistance. (C) 1996 by The American Society of Hematology.