Ohtaka Mika, Itoh Mai, Tohda Shuji
Department of Laboratory Medicine, Tokyo Medical and Dental University, Tokyo, Japan.
Department of Laboratory Medicine, Tokyo Medical and Dental University, Tokyo, Japan
Anticancer Res. 2017 Nov;37(11):6047-6053. doi: 10.21873/anticanres.12052.
BACKGROUND/AIM: B cell-specific Moloney murine leukemia virus integration site 1 (BMI1) is up-regulated in several cancers; therefore, we investigated the effects of BMI1 inhibitors on leukemia cells.
Four acute myeloid leukemia and two T-lymphoblastic leukemia cell lines were treated with BMI1 inhibitors artemisinin, PRT4165, and PTC-209 and analyzed for cell proliferation and gene expression by microarray and immunoblotting.
PTC-209 and PRT4165 suppressed the growth of all cell lines through apoptosis.Artemisinin acted only on Jurkat cells. BMI1 inhibitors and BMI1-specific siRNA down-regulated the expression of NOTCH signaling proteins NOTCH1, HES1, and MYC. All but one cell lines did not have the cyclin-dependent kinase inhibitor 2A (CDKN2A) gene targeted by BMI1, thus the inhibitors acted through CDKN2A-independent pathways.
BMI1 inhibition suppressed proliferation of leukemia cells through NOTCH signaling which functions downstream of BMI1, suggesting that BMI1 inhibitors can be candidate targeted drugs against leukemia.
背景/目的：B细胞特异性莫洛尼鼠白血病病毒整合位点1（BMI1）在多种癌症中上调；因此，我们研究了BMI1抑制剂对白血病细胞的影响。
用BMI1抑制剂青蒿素、PRT4165和PTC-209处理四种急性髓系白血病细胞系和两种T淋巴细胞白血病细胞系，并通过微阵列和免疫印迹分析细胞增殖和基因表达。
PTC-209和PRT4165通过凋亡抑制所有细胞系的生长。青蒿素仅作用于Jurkat细胞。BMI1抑制剂和BMI1特异性小干扰RNA下调NOTCH信号蛋白NOTCH1、HES1和MYC的表达。除一个细胞系外，所有细胞系均无BMI1靶向的细胞周期蛋白依赖性激酶抑制剂2A（CDKN2A）基因，因此抑制剂通过不依赖CDKN2A的途径发挥作用。
BMI1抑制通过BMI1下游发挥作用的NOTCH信号抑制白血病细胞增殖，提示BMI1抑制剂可作为抗白血病的候选靶向药物。
