Antimyeloma activity of bromodomain inhibitors on the human myeloma cell line U266 by downregulation of MYCL.
Antimyeloma activity of bromodomain inhibitors on the human myeloma cell line U266 by downregulation of MYCL.
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DOI：
10.1097/cad.0000000000000389
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发表时间：
2016-09
影响因子：
2.3
通讯作者：
Kitagawa M
中科院分区：
文献类型：
--
作者：
Suzuki K;Yamamoto K;Arakawa Y;Yamada H;Aiba K;Kitagawa M
补充数字内容可在文本中找到。溴结构域和末端外蛋白（BET）抑制剂抑制c-MYC的表达。人骨髓瘤细胞系U266表达MYCL基因，但不表达c-MYC基因。我们的目的是分析BET抑制剂对U266细胞的抗骨髓瘤活性。测试了两种BET抑制剂I-BET 151和JQ 1。用MTS四唑盐处理，500 nmol/l I-BET 151孵育72和96 h后，U266细胞增殖分别降至对照的61.5%和54.0%，500 nmol/l JQ 1孵育72和96 h后，分别降至对照的53.5%和56.4%。BET抑制剂诱导细胞周期停滞在G1期的U266细胞，但不诱导凋亡的流式细胞术。基因集富集分析显示，与表达c-MYC的KMS 11细胞相似，I-BET 151处理的U266细胞中MYC相关基因表达显著下调。实时荧光定量RT-PCR检测结果显示，MYCL 1在U266细胞中有表达，而c-MYC和MYCN在U266细胞中无表达。用I-BET 151孵育诱导U266细胞中MYCL 1的下调。BET抑制剂对MYCL过表达的U266细胞增殖的抑制作用小于未过表达的细胞。BET抑制剂诱导G1期阻滞而无细胞凋亡，并干扰表达MYCL但不表达c-MYC的U266骨髓瘤细胞的增殖。BET抑制剂可能在表达MYCL但不表达c-MYC的癌症中具有活性。
Supplemental Digital Content is available in the text. Bromodomain and extraterminal protein (BET) inhibitors suppress the expression of c-MYC. U266, a human myeloma cell line, expresses the MYCL gene, but not the c-MYC gene. Our aim was to analyse the antimyeloma activity of BET inhibitors on U266 cells. Two BET inhibitors, I-BET151 and JQ1, were tested. U266 cell proliferation decreased to 61.5 and 54.0% of the control after incubation with 500 nmol/l I-BET151 for 72 and 96 h and to 53.5 and 56.4% of control after incubation with 500 nmol/l JQ1 for 72 and 96 h by MTS tetrazolium, respectively. BET inhibitors induced cell cycle arrest at the G1 phase in U266 cells, but did not induce apoptosis by flow cytometry. According to Gene Set Enrichment Analysis, MYC-related genes were significantly downregulated in U266 cells treated with I-BET151 similar to KMS11 cells that expressed c-MYC. The MYCL1 was expressed in U266 cells, whereas c-MYC and MYCN were not by quantitative real-time reverse-transcription-PCR. Incubation with I-BET151 induced downregulation of MYCL1 in U266 cells. BET inhibitors decreased the cell proliferation in U266 cells with overexpression of MYCL less than those without overexpression of MYCL. BET inhibitors induce G1 arrest without apoptosis and interfere with the proliferation of U266 myeloma cells, which express MYCL, but not c-MYC. BET inhibitors might be active in cancers that express MYCL, but not c-MYC.