Increased susceptibility to apoptosis in CD45+ myeloma cells accompanied by the increased expression ofVDAC1
Increased susceptibility to apoptosis in CD45+ myeloma cells accompanied by the increased expression ofVDAC1
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DOI：
10.1038/sj.onc.1208982
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发表时间：
2006-01-01
期刊：
影响因子：
8
通讯作者：
Kawano, MM
中科院分区：
文献类型：
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作者：
Liu, S;Ishikawa, H;Kawano, MM
CD45在人类骨髓瘤细胞和细胞系中的表达差异很大，如U266，CD45(+)U266在生长因子IL-6的作用下增殖。在这里，我们显示CD45(+)骨髓瘤细胞系对各种凋亡刺激，如氧化应激和内质网(ER)应激比CD45(-)细胞更敏感。CD45(+)U266细胞对凋亡的敏感性可能与活性氧和钙离子有关。CD45磷酸酶相关的src家族激酶的激活在氧化应激促进CD45(+)U266细胞的凋亡中起着重要作用。这些结果表明，CD45-表达使骨髓瘤细胞不仅对有丝分裂刺激，而且对凋亡刺激，导致CD45(+)骨髓瘤细胞的增殖或凋亡依赖于环境刺激。此外，通过cDNA消减，发现电压依赖性阴离子通道(VDAC)1是CD45(+)U266中高表达的基因。VDAC1表达的增加似乎增加了对内质网应激的敏感性，因为VDAC1转基因的U266对thapsigargin诱导的细胞凋亡更敏感。因此，CD45的表达伴随着VDAC1表达的增加，使骨髓瘤细胞对各种细胞外刺激敏感，这些细胞外刺激通过线粒体途径触发细胞凋亡。
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 thapsigargininduced 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.