Liu S, Ishikawa H, Tsuyama N, Li F-J, Abroun S, Otsuyama K-I, Zheng X, Ma Z, Maki Y, Iqbal M S, Obata M, Kawano M M
Laboratory of Cellular Signal Analysis, Department of Bio-Signal Analysis, Applied Medical Engineering Science, Graduate School of Medicine, Yamaguchi University, 1-1-1 Minami-kogushi, Ube, Yamaguchi 755-8505, Japan.
Oncogene. 2006 Jan 19;25(3):419-29. doi: 10.1038/sj.onc.1208982.
Expression of CD45 is quite variable in human myeloma cells and cell lines, such as U266, and CD45(+) U266 proliferates in response to a growth factor, interleukin-6. Here, we show that CD45(+) myeloma cell lines were more sensitive to various apoptotic stimuli, such as oxidative stress and endoplasmic reticulum (ER)-stress, than CD45(-) cells. Reactive oxygen species and calcium ion seemed to be involved in the susceptibility to apoptosis of CD45(+) U266. The activation of the src family kinases associated with CD45 phosphatase played an important role in the augmented apoptosis in CD45(+) U266 by oxidative stress. These results indicate that the CD45-expression renders myeloma cells competent for not only mitogenic but also apoptotic stimuli, resulting in either proliferation or apoptosis of CD45(+) myeloma cells dependently upon the circumstantial stimuli. Furthermore, voltage-dependent anion channel (VDAC) 1 was identified as a gene highly expressed in CD45(+) U266 by cDNA subtraction. The increased expression of VDAC1 seemed to augment the sensitivity to the ER-stress because the VDAC1-transfected U266 was more susceptible to the thapsigargin-induced apoptosis. Thus, CD45 expression accompanied by the increased VDAC1 expression sensitizes myeloma cells to the various extracellular stimuli that trigger apoptosis via the mitochondrial pathways.
CD45在人骨髓瘤细胞和细胞系（如U266）中的表达变化很大，并且CD45(+) U266会响应生长因子白细胞介素-6而增殖。在此，我们表明，与CD45(-)细胞相比，CD45(+)骨髓瘤细胞系对各种凋亡刺激（如氧化应激和内质网（ER）应激）更敏感。活性氧和钙离子似乎与CD45(+) U266对凋亡的易感性有关。与CD45磷酸酶相关的src家族激酶的激活在氧化应激导致的CD45(+) U266凋亡增加中起重要作用。这些结果表明，CD45的表达使骨髓瘤细胞不仅能对促有丝分裂刺激作出反应，还能对凋亡刺激作出反应，导致CD45(+)骨髓瘤细胞根据环境刺激而增殖或凋亡。此外，通过cDNA消减技术，电压依赖性阴离子通道（VDAC）1被鉴定为在CD45(+) U266中高表达的基因。VDAC1表达的增加似乎增强了对ER应激的敏感性，因为转染了VDAC1的U266对毒胡萝卜素诱导的凋亡更敏感。因此，CD45表达伴随着VDAC1表达的增加，使骨髓瘤细胞对通过线粒体途径触发凋亡的各种细胞外刺激敏感。
